Cristae Formation—Linking Ultrastructure and Function of Mitochondria

Home , Crista

View metadata, citation and similar papers at core.ac.uk brought to you by CORE

provided by Elsevier - Publisher Connector

Biochimica et Biophysica Acta 1793 (2009) 5–19

Contents lists available at ScienceDirect

Biochimica et Biophysica Acta

journal homepage: www.elsevier.com/locate/bbamcr

Review Cristae formation—linking ultrastructure and function of mitochondria

Michael Zick a, Regina Rabl a, Andreas S. Reichert b,⁎

a Adolf-Butenandt-Institut für Physiologische Chemie, Ludwig-Maximilians-Universität München, Butenandtstr. 5, 81377 München, Germany b CEF Makromolekulare Komplexe, Mitochondriale Biologie, Fachbereich Medizin, Goethe-Universität Frankfurt am Main, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany

article info abstract

Article history: Mitochondria are double-membrane enclosed eukaryotic organelles with a central role in numerous cellular Received 4 March 2008 functions. The ultrastructure of mitochondria varies considerably between tissues, organisms, and the Received in revised form 5 June 2008 physiological state of cells. Alterations and remodeling of inner membrane structures are evident in Accepted 12 June 2008 numerous human disorders and during apoptosis. The inner membrane is composed of two subcompart- Available online 20 June 2008 ments, the cristae membrane and the inner boundary membrane. Recent advances in electron tomography led to the current view that these membrane domains are connected by rather small tubular structures, Keywords: Mitochondria termed crista junctions. They have been proposed to regulate the dynamic distribution of proteins and lipids Cristae formation as well as of soluble metabolites between individual mitochondrial subcompartments. One example is the Crista junction release of cytochrome c upon induction of apoptosis. However, only little is known on the molecular Electron tomography mechanisms mediating the formation and maintenance of cristae and crista junctions. Here we review the Apoptosis current knowledge of the factors that determine cristae morphology and how the latter is linked to Mitochondrial dynamics mitochondrial function. Further, we formulate several theoretical models which could account for the de novo formation of cristae as well as their propagation from existing cristae. © 2008 Elsevier B.V. All rights reserved.

1. Introduction Mitochondria are surrounded by two membranes: the outer membrane (OM) and the inner membrane (IM). Within the inner Mitochondrial research has influenced numerous scientific dis- membrane two distinct regions can be distinguished: the inner ciplines over the last 150 years [1,2]. These organelles have been boundary membrane (IBM) and the cristae membrane (CM). The IBM morphologically described as threads (German, ‘Faden’; Greek ‘mitos’) is adjacent to the outer membrane whereas the CM represents or grains (German, ‘Körper’; Greek ‘chondros’) in various tissues as invaginations of the IBM that protrude into the matrix space. This view early as in the 1850s leading to the name ‘Fadenkörper’ (German) or of a double-membrane enclosed organelle with inner membrane ‘mitochondria’ (Greek). Initially, mitochondrial research was focused convolutions was established with the pioneering work in electron on a number of fundamental metabolic and bioenergetic functions, microscopy of Palade and Sjöstrand in the 1950s [9]. It quickly became such as oxidative phosphorylation (OXPHOS), Krebs cycle, heme clear that mitochondria exhibit an extremely large variability of biosynthesis, β-oxidation of fatty acids, and the metabolism of certain ultrastructures depending on the tissue, the physiological state, and amino acids [2]. The discovery of mitochondrial DNA in the 1960s the developmental stage [10,11]. Tubular, lamellar and even triangle- fueled the scientific discussion about the evolution of mitochondria by shaped cristae membranes (Fig. 1) have been observed [10–12]. endosymbiosis [3]. More recently, targeting and import of proteins Alterations of mitochondrial structures, often accompanied by inclu- into mitochondria [4], biogenesis of Fe/S clusters [5], and the role of sions or aggregates in the mitochondrial matrix, are well known for mitochondria in controlling apoptosis in higher eukaryotes [6] numerous diseases in humans. For example, in lymphoblasts of have substantially extended the interest in mitochondrial research. patients suffering from Barth syndrome mitochondria appear In light of the fundamental roles of mitochondria it is not unexpected enlarged with grossly reduced inner membrane surface area [13]. that dysfunction of this organelle is linked to a wide range of human They mostly exhibit a few but deranged cristae, while also several diseases, including numerous neuropathies and myopathies [7]. giant mitochondria with a completely disorganized inner membrane Furthermore, the accumulation of mutations in mitochondrial DNA topology, in particular concentric stacks of inner membrane or was shown to result in premature ageing of mice [8] providing honeycomb configurations, have been observed. Barth syndrome is a compelling evidence that mitochondrial dysfunction not only pre- mitochondrial disorder caused by mutations in tafazzin [14], which is cedes but also has to be considered as a causative factor in aging of involved in the biosynthesis of mitochondrial phospholipids such as mammals. cardiolipin [15]. This indicates that certain phospholipids are crucial for maintaining mitochondrial ultrastructure. Also in Alzheimer's ⁎ Corresponding author. Tel.: +49 69 6301 87135; fax: +49 69 6301 87162. disease mitochondrial morphology is altered in such a way that E-mail address: [email protected] (A.S. Reichert). cristae are disrupted, and inclusions within mitochondria and varying

Fig. 1. Diversity of mitochondrial ultrastructures. Different types of cristae are shown from various tissues under normal (A–D) or pathogenic conditions (E, F): (A) Adrenal cortex. (B) Astrocyte. (C) Fish pseudobranch. (D) Ventricular cardiac muscle (A–D taken from [10]). (E and F). Chronic polymyositis with Raynaud's syndrome (taken from [30]). types of inner membrane arrangements including concentric and 2. Mitochondrial architecture — changing views parallel stacks of cristae membranes were observed [16]. Inclusions and altered cristae morphology were also found in the skeletal muscle The use of electron microscopy in the 1950s boosted mitochondrial of patients with amyotrophic lateral sclerosis [17]. Several other research considerably as it allowed novel insights into the internal examples of human diseases with alterations of mitochondrial structure of mitochondria. However, determining and interpreting morphology have been reported (see Table 1), such as Parkinson's ultrastructural details of mitochondria is a challenging task. On the disease [18–22], Wolf–Hirschhorn syndrome [23–25], Wilson disease one hand it is desirable to obtain high resolution of structural details. [26–28], 3-methylglutaconic aciduria [29], chronic polymyositis [30], On the other hand mitochondria are rather large, elongated tubular and hereditary mitochondrial hypertrophic cardiomyopathy [31]. structures within the cytosol covering the length of up to several Here, we aim to review our current understanding on how hundred µm making the simultaneous analysis of larger volumes mitochondrial function and structure are linked to each other and, difﬁcult. For the elucidation of small membrane structures the use of particularly, what molecular mechanisms are known to mediate electron microscopy is the method of choice. However, sections used cristae formation. for electron microscopy have a certain thickness of at least 5 but M. Zick et al. / Biochimica et Biophysica Acta 1793 (2009) 5–19 7

Table 1 Candidate proteins determining cristae morphology

Protein (organism) Aberration of mitochondrial Assigned function Associated human disorder References ultrastructure Atp21p/Tim11p (su e), Onion-like, elongated cristae Dimerization and higher order – [4,84,85,87–89] Atp20p (su g), Atp4p oligomerization components of the

(S. cerevisiae) F1FO-ATP synthase

ATP6/Atp6p (H. sapiens, Aberrant mitochondrial morphology; Proton channel of F1FO-ATP synthase Neuropathy, ataxia and [95,98,100] D. melanogaster, IM vesicles, septa retinitis pigmentosa (NARP), S. cerevisiae) maternally inherited Leigh syndrome (MILS) PINK1 (H. sapiens, C. elegans, Swollen mitochondria; cristae Mitochondrial serine/threonine kinase "; Parkinson's disease [18,174,178] D. melanogaster) fragmentation Tafazzin (H. sapiens) Fragmentation of mitochondria; Acyltransferase involved in the Barth syndrome (BTHS) [13,73] reduced cristae surface biosynthesis of mitochondrial phospholipids DICE1/DIC-1 (H. sapiens, Aberrant IM ultrastructure, Tumor suppressor protein Various types of cancer [18, 153–155] C. elegans) IM vesiculation (e.g. lung carcinoma, prostate cancer) AIF (M. musculus) Aberrant IM topology Induction of apoptosis – [152] Mdm33p (S. cerevisiae) Aberrant mitochondria; overexpression Fission of inner mitochondrial membrane – [163] leads to loss of cristae Mmm1p (S. cerevisiae) Spherical mitochondria; disorganization Maintenance of mtDNA; import and – [164,165,169] of IM assembly of beta-barrel proteins LETM1/Mdm38p (H. sapiens, Osmotic swelling; loss of membrane K+/H+ exchange; chaperone for Wolf–Hirschhorn syndrome [24,170,171] D. melanogaster, C. elegans; potential; mitochondrial fragmentation mitochondrial IM proteins S. cerevisiae) OPA1/Mgm1p (H. sapiens; Cristae remodeling during apoptosis; Remodeling of CJs; inner membrane fusion; Autosomal dominant optic [119,123, 124, 126] M. musculus; S. cerevisiae) reduction in observable normal cristae; cristae maintenance atrophy (ADOA) accumulation of septa Prohibitins (PHB1/Phb1p, Loss of cristae and vesiculation of the IM Various cellular functions; mtDNA Various forms of cancer [129,183, 204–206] PHB2/Phb2p) (H. sapiens; maintenance; regulation of mitochondrial M. musculus; S. cerevisiae) protein turnover; regulation of OPA1 processing, membrane bound chaperon Mitoﬁlin (H. sapiens) Absence of CJs; disorganization Organization of cristae and CJs Down syndrome [184,188] of the IM; increased IM:OM ratio

Abrogating the function of these proteins leads to aberrations of mitochondrial ultrastructure. Thus, they are presumed to be directly or indirectly involved in cristae formation. Some of these proteins have been linked to a human disorder (see text). Proteins with a causative role in human disease are highlighted in bold. OM, outer membrane; IM, inner membrane; CJs, crista junctions. usually 30 to 100 nm. Thus, even when very thin serial sections are resolution. Several studies revealed that cristae are attached to the used for the reconstruction of a mitochondrial volume a low IBM by narrow, tubular openings which were termed “crista resolution along the z-axis and distortion of the obtained reconstruc- junctions” (CJs) [39–43]. CJs are present in mitochondria of various tions along this dimension remains. This severely limits the conclu- tissues and organisms, such as neurons from chicken, rat, and mouse sions that can be drawn from the analysis of serial sections of [44,45], brown adipocytes [46], human lymphoblasts [13], Neurospora mitochondria and may explain the controversial discussion concern- crassa [47,48], and Saccharomyces cerevisiae (Fig. 3). Although a wide ing the arrangement of inner membrane structures in mitochondria in spectrum of cristae appearances has been described, CJs rather appear the last decades. Several hypothetical models have been proposed to exhibit uniform sizes and shapes. The narrow tubular, ring- or slot- (Fig. 2), among them the one of Palade which confirmed the existence like structures exhibit diameters ranging from 12 to 40 nm [41,45,47]. of an outer and an inner membrane and suggested the inner While most CJs measure 30 to 50 nm in length, also longer specimens membrane to be folded into “cristae mitochondriales” [32,33].In measuring 150–200 nm have been observed in N. crassa [47]. this ‘baffle model’ cristae are regarded as invaginations of the inner Condensation of the matrix space of a mitochondrion (“condensed membrane with rather broad openings (Fig. 2A). Another interpreta- state”) results in the appearance of CJs in comparison to a tion of the appearance of inner membrane structures as observed in mitochondrion subjected to osmotic swelling of the matrix space sections of electron micrographs was proposed by Sjöstrand as the (“orthodox state”). As this appears to be reversible a dynamic ‘septa model’ [34,35]. Thereby, the surface of the inner membrane is formation of CJs was proposed [42]. Inhibiting mitochondrial protein increased due to the formation of septa (Fig. 2B). Opposing views to import in N. crassa led to a simultaneous reduction of cristae these models existed already more than 50 years ago [36–38]. With membranes and CJs [48]. Remnants of CJs, however, were not the analysis of very thin serial sections of mitochondria by transmis- observed indicating that CJs are not permanent structures. Although sion electron microscopy Daems and Wisse (1966) identified small more and more structural details on CJs become available it is still tubular structures connecting cristae with the IBM which they named open what the functional significance of these structures is. pediculi cristae (“crista feet”). Although this view did not achieve acceptance and rather the ‘baffle model’ entered most textbooks it 3. Subcompartmentalization of the inner mitochondrial recently obtained strong support when Mannella and colleagues membrane applied electron tomography (EM tomography) to determine the mitochondrial ultrastructure of isolated rat liver mitochondria [39,40]. One idea was that CJs play a crucial role in establishing inner- EM tomography allows the three-dimensional reconstruction of mitochondrial subcompartments [40]. They could represent diffusion volumes of rather thick sections (∼0.5 µm). For this a series of barriers between the intermembrane space (IMS) and the intracristal electron micrographs is recorded while the sample is tilted over a space (ICS) as well as between the IBM and the CM. A possible wide range of angles. By computational analysis the three-dimen- consequence would be to prevent or limit diffusion of metabolites sional structure of the entire specimen can be reconstructed at a high such as protons and ADP [43,44]. This would indeed be of gross impact 8 M. Zick et al. / Biochimica et Biophysica Acta 1793 (2009) 5–19

characterizations of these subcompartments together with membrane domains, termed contact sites, in which the outer membrane closely apposes the IBM [51–54]. However, these approaches require the isolation and rupture of mitochondria making it difficult to exclude any artificial redistribution of protein complexes during analysis [55]. Still, these studies and the localization of certain marker proteins in isolated mitochondria by using electron microscopy suggested the CM to be the preferential site of oxidative phosphorylation [56,57]. Furthermore, two recent studies using whole cells and a larger set of marker proteins provided strong support that the inner membrane is indeed composed of two subcompartments [50,58]. By using mutants with enlarged mitochondria Wurm and Jakobs were able to determine the submitochondrial location of a number of proteins in baker's yeast using fluorescence microscopy [58]. Components involved in oxidative phosphorylation clearly stained the interior and thus the CM of mitochondria, whereas proteins involved in protein translocation stained the periphery and thus the IBM of mitochondria. A systematic approach using quantitative immunoelectron microscopy in intact wild type yeast cells also revealed an uneven, yet not exclusive, distribution of proteins in the inner mitochondrial membrane [50]. In total 20 inner membrane proteins representing seven major processes (oxidative phosphorylation, protein translocation, metabolite exchange, mitochondrial morphology, protein translation, iron/sulfur cluster biogenesis, and protein degradation) were analyzed (Fig. 4). The CM was enriched in proteins Fig. 2. Models of mitochondrial inner membrane topology. With the discovery of the involved in oxidative phosphorylation, iron/sulfur cluster biogenesis, dual membrane nature of mitochondria the pioneers of mitochondrial ultrastructural research proposed different models for the organization of the mitochondrial inner protein synthesis and transport of mtDNA-encoded proteins, whereas membrane. (A) ‘Baffle model’. According to Palade [32,33] the mitochondrial inner the IBM was enriched in proteins involved in mitochondrial fusion and membrane is convoluted in a baffle-like manner with broad openings towards the protein transport of nuclear-encoded proteins. Furthermore, a intracristal space. This model entered most textbooks and was widely believed for a dynamic redistribution of these proteins between the two compart- long time. (B) ‘Septa model’. Sjöstrand suggested that sheets of inner membrane are spanned like septa trough the matrix separating it into several distinct compartments ments of the inner membrane was shown to occur upon changes in [34]. (C) ‘Crista junction model’. Daems and Wisse [38] proposed that cristae are the physiological state [50]. Under steady-state conditions Tim23p, an connected to the inner boundary membrane via tubular structures characterized by essential component for mitochondrial protein import, is preferen- rather small diameters. These structures, termed crista junctions (CJs), were tially found in the IBM. This enrichment is slightly increased when rediscovered recently by EM tomography leading to the establishment of this currently import is stimulated upon overexpression of a mitochondrial protein widely accepted model [39,40]. and, conversely, Tim23p redistributes partially to the CM when import is arrested due to inhibition of cytosolic protein synthesis. Apparently, for the regulation of oxidative phosphorylation as one key limiting Tim23p can dynamically relocate within the inner membrane opening metabolite is ADP. Thus, the shape and size of CJs could contribute to the possibility that the CM may also act as a kind of reservoir for the regulation of the rates of ATP production by limiting ADP flux protein complexes functioning in the IBM. [39,41]. Moreover, the diffusion of large protein complexes within the Another example for the dynamics of large protein complexes in lipid bilayer of the inner membrane could be regulated by CJs. In the inner membrane was obtained from analyzing a yeast mutant particular, oligomeric complexes might be prone to be trapped in one (Δbcs1) defective in the assembly of complex III and of the super- or the other subcompartment [44,49,50]. The idea of distinct complex of complex III and IV. While in wild type the fully assembled subcompartments within the mitochondrial inner membrane is not complex III is mostly present in the CM, in the Δbcs1 mutant the non- new and has been discussed since IBM and CM could be distinguished assembled Fe/S-Rieske protein subunit of complex III partially morphologically by electron microscopy. The biochemical fractiona- redistributes to the IBM [50]. It is interesting to note that this subunit tion of submitochondrial membrane vesicles allowed the first is also nuclear-encoded and thus preferentially imported at the IBM,

Fig. 3. Cryo-EM tomogram of a crista junction in Saccharomyces cerevisiae. (A) Single slice through a tomogram of an isolated vitriﬁed wild type mitochondrion from S. cerevisiae. (B) Magniﬁed view of boxed area in left panel. (C) Surface rendered view of a crista junction. Scale bars 100 nm. EM tomogram with courtesy of Dr Marek Cyrklaff. M. Zick et al. / Biochimica et Biophysica Acta 1793 (2009) 5–19 9

Fig. 4. Subcompartmentalization of the mitochondrial inner membrane. The distribution of mitochondrial proteins involved in several major processes of mitochondria has been determined by quantitative immunoelectron microscopy in S. cerevisiae [50]. Inner membrane proteins involved in mitochondrial fusion (Mgm1p) or protein translocation (Mia40p,

TIM23 complex) are preferentially located in the inner boundary membrane. In contrast, proteins involved in oxidative phosphorylation (ANC, Complex III, Complex IV, F1FO-ATP synthase) and in iron/sulfur cluster biogenesis (Fe/S cluster) are enriched in the cristae membrane. This distribution is uneven, yet not exclusive nor static. Proteins dynamically redistribute between the domains depending on the physiological state of the cell. CS, Cytosol; OM, outer membrane; IMS, intermembrane space; IM, inner membrane; M, matrix space. Style adapted from the illustrations of Graham T. Johson in [203]. whereas Cox2p is mtDNA-encoded and might, based on the afore- of the mitochondrial inner membrane were proposed to lead to an mentioned results, be preferentially imported and inserted in the CM. increase in membrane surface and thus to enhance the capacity of This subunit of complex IV is more enriched in the CM in the Δbcs1 oxidative phosphorylation [32]. This is in line with the, compared to mutant as compared to the wild type. Although these observations do other biological membranes, extremely high ratio of protein to lipid not allow any conclusion concerning the question in which sub- mass (∼75:25) of the mitochondrial inner membrane [1]. The largest compartment the supercomplex III2IV2 actually assembles, it still proportion of these proteins is involved in oxidative phosphorylation points to the possibility that a coordinated insertion of protein and the surface area of cristae positively correlates with the amount of subunits in distinct locations of the inner membrane is important for ATP produced by oxidative phosphorylation in various tissues. The proper assembly and localization of respiratory chain complexes. mitochondrial CM further was hypothesized to serve as a specialized Taken together, the observed protein distributions are dynamic and compartment ensuring optimal conditions for ATP production [32]. correlate with the known function of the analyzed components. This How could cristae formation be accomplished on a molecular level dynamic behavior at the inner mitochondrial level extends our and what could be the benefit of this process that goes beyond a mere concept of CJs which might not function as strict diffusion barriers surface increase? Based on a mathematical model Demongeot et al. to membrane proteins as previously assumed. Unraveling the under- recently suggested as one function of mitochondrial cristae their lying molecular mechanisms leading to distinct subcompartments of capacity to minimize the mean distance between adenine nucleotide the mitochondrial inner membrane, but still allowing a dynamic translocation and transformation sites for highest efficiency of ATP reorganization between these domains, will be one important future production [59]. In addition, long before Mitchell formulated the challenge in mitochondrial research. chemiosmotic theory of oxidative phosphorylation [60], the arrangement of the respiratory chain within the inner membrane was 4. Cristae morphology from a bioenergetic point of view proposed to be dependent “on a definite, spatial arrangement of its individual components and thus on the structural integrity of the One of the main functions of mitochondria is the use of dietary mitochondrion” [61]. In the meantime, complexes of the respiratory calories to synthesize ATP. By the action of the respiratory chain an chain have been shown to form large supermolecular assemblies, electrochemical gradient across the inner mitochondrial membrane is termed respiratory supercomplexes or ‘respirasomes’, [62–67]. This established which serves as the driving force for the production of ATP type of organization was hypothesized to be of high functional from ADP and inorganic phosphate by the mitochondrial F1FO-ATP importance for optimizing electron transport during respiration synthase. Already in the 1950s, after the first visualizations of [66,68,69]. However, whether respiratory chain supercomplexes also mitochondrial ultrastructures by electron microscopy, convolutions participate in determining the structure of cristae is an open question. 10 M. Zick et al. / Biochimica et Biophysica Acta 1793 (2009) 5–19

Cardiolipin, an acidic phospholipid almost exclusively found in certain ultrastructures facilitate fundamental mitochondrial func- mitochondrial membranes, has also been implicated in contributing to tions, or whether cristae are dynamic structures. the characteristic shape of the mitochondrial inner membrane.

Mitochondria of patients suffering from Barth syndrome exhibit an 5. Role of the F1FO-ATP synthase in cristae formation 80% reduction in cardiolipin content which is accompanied by severe ultrastructural changes of the mitochondrial inner membrane Since a few years there is strong evidence that the mitochondrial topology [13,70–72]. Cardiolipin has been reported to stabilize F1FO-ATP synthase, apart from its enzymatic activity, plays a major supercomplexes of the respiratory chain as revealed by blue native role in determining the structure of cristae. In Paramecium multi- gel electrophoresis of detergent-solubilized mitochondria [73–75]. micronucleatum a regular, zipper-like association of F1FO-ATP synthase Thus, it remains to be elucidated whether cardiolipin exerts a direct dimers surrounding tubular cristae was observed [81]. The association inﬂuence on the inner membrane curvature or rather affects inner of F1FO-ATP synthase dimers into higher order oligomers was membrane topology via stabilizing higher order enzymatic com- proposed to be responsible for the tubulation of the mitochondrial plexes. In the 1970s, structural changes in mitochondria have also inner membrane [82]. The regular arrangement of this highly been ascribed to the inhibition of the adenine nucleotide carrier (ANC) abundant protein complex might serve as a kind of backbone by Klingenberg and colleagues [76]. This was hypothesized to be stabilizing tubular cristae structures. Subunits e (Atp21p/Tim11p) caused by redistribution or conformational changes of ANC upon and g (Atp20p) are components of the mitochondrial F1FO-ATP inhibition [76,77]. However, later Klingenberg himself questioned synthase which are neither essential for ATP synthesis nor hydrolysis, whether the carrier protein alone could explain the observed mor- but crucial for the dimerization and higher order oligomerization of phological changes [78]. the F1FO-ATP synthase [83]. It was reported that yeast cells either Hackenbrock was the ﬁrst to show that the topology of the lacking subunits e or g contain cristae membranes which are arranged mitochondrial inner membrane is subjected to extensive morpholo- in concentric circles resembling an onion-like structure [84–86] (Fig. gical changes depending on the respiratory state of mitochondria 5A). Downregulation of these subunits revealed similar results [87]. [79,80]. In respiratory state III, which is characterized by an excess of Also mutant variants of subunit 4, orthologous to the b-subunit in

ADP, isolated rat liver mitochondria showed a condensed conforma- mammals, lead to a destabilization of the F1FO-ATP synthase dimers/ tion with large swollen intra-cristal space volume, while under ADP oligomers and to onion-like cristae structures in yeast [88,89]. In vivo limiting conditions (respiratory state IV) this volume was considerably cross-linking of F1FO-ATP synthases via their F1-portions resulted in a smaller, characteristic for the orthodox conformation. Based on similar ultrastructural phenotype [90] further emphasizing the crucial simulations, Mannella and colleagues speculated that this dynamic role of the oligomerization of this protein complex in determining morphological shift could optimize diffusion of metabolites [42].In normal inner membrane topology. summary, mitochondrial ultrastructure is clearly linked to the Currently the nature and importance of possible interfaces bioenergetic state of mitochondria. However, so far little is known mediating dimerization and oligomerization of this complex are about the key factors that actually determine cristae structure, how hotly debated. Paumard and colleagues proposed a model for the

Fig. 5. Role of the dimerization and oligomerization of the F1FO-ATP synthase in cristae formation. (A) Electron micrograph of a yeast mitochondrion lacking subunit e of the F1FO-ATP synthase (with courtesy of Dr Frank Vogel). Cristae exhibit typical onion-like inner membrane sheets in this mutant in which also dimerization and oligomerization of the F1FO-ATP synthase is strongly impaired. (B) Model for the induction of membrane curvature by dimers of the F1FO-ATP synthase. A dimer of the mitochondrial F1FO-ATP synthase of baker's yeast with its monomers tilted by 35° [102] is depicted in side view (adapted from the illustrations of Graham T. Johson in [203]). Dimers of this complex have been observed for several organisms; however the tilt angle between monomers varies considerably. (C) Putative arrangement of F1FO-ATP synthase oligomers shown as top view (adapted from [85]). Subunits e and g may stabilize dimers by forming one interaction interface, and subunit 4 could be involved in forming another interface to interconnect these dimers into higher order oligomeric complexes. However, the role of other subunits in the formation or stabilization of F1FO-ATP synthase dimers and oligomers is currently debated. IMS, intermembrane space; IM, inner membrane; M, matrix. M. Zick et al. / Biochimica et Biophysica Acta 1793 (2009) 5–19 11

association of F1FO-ATP synthase dimers in which two different question [102]. Dudkina et al. propose that the two conformations of interfaces are responsible for the association of F1FO-ATP synthase F1FO-ATP synthase dimers could result from different breakdown monomers through their FO-portions. The ﬁrst one is composed of products of F1FO-ATP synthase oligomers that interact via different subunits e and g, the second one involves subunit 4 (subunit b)(Fig. domains [102].

5C). The roles of subunits e and g in dimer formation in vivo were Rows of F1FO-ATP synthase dimers were recently observed in challenged as also in the absence of subunits e or g a physical membrane fractions from yeast mitochondria using atomic force neighborhood between monomers of the F1FO-ATP synthase could be microscopy [105]. These rows were similar to the ones described in P. observed using FRET (fluorescence resonance energy transfer) [91] or multimicronucleatum with rapid-freeze deep-etch electron micro- cross-linking approaches [92]. However, this still would be consistent scopy [81] (Fig. 5C). Buzhynskyy et al. observed two classes of F1FO- with the perpetuation of an alternative interface such as the one ATP synthase dimers and propose that one class represents active exerted by subunit 4. Also downregulation of subunit h resulted in a F1FO-ATP synthase dimers, while the other one is inactive [105]. loss of F1FO-ATP synthase dimers/oligomers accompanied by clear Several reports discuss the possibility that dimerization and oligo- topological changes of the mitochondrial inner membrane [93]. Wittig merization of this complex inflicts a certain membrane curvature to et al. recently proposed that subunit 6 (a) forms stable dimers and the CM [102,103,106] (Fig. 5B). Recently, it has been speculated that mediates the interaction between two subunit 910-rings (c10) of the such a spatial arrangement results in a membrane curvature that F1FO-ATP synthase which is further stabilized through subunits e.g., 4, locally increases the pH gradient and in this way the F1FO-ATP i, and h [94]. Using clear native polyacrylamide gel electrophoresis synthase would optimize its own performance by shaping cristae as (CN-PAGE) the same authors provided first evidence that indeed the proton traps [106]. Furthermore, Bornhövd et al. have shown that the dimers of the F1FO-ATP synthase are the building blocks of oligomers, stability of F1FO-ATP synthase oligomers affects the mitochondrial as most oligomeric forms contain an even number of monomers [94]. membrane potential ΔΨ, and have put forward the hypothesis that

A recent study by Celotto et al. has revealed ultrastructural defects of F1FO-ATP synthase supercomplexes may play a role in the organization the mitochondrial inner membrane in Drosophila cells harboring a of microdomains of OXPHOS complexes within the inner mitochon- mutation in the mitochondrial ATP6 gene [95]. This subunit is an drial membrane [86]. Still, further studies are needed to answer which essential component of the mitochondrial F1FO-ATP synthase that advantage a higher order oligomerization of the F1FO-ATP synthase functions as a proton channel coupling the proton motive force to ATP actually provides to the bioenergetic function of mitochondria. synthesis [96,97]. Point mutations within the ATP6 gene are linked to several encephalomyopathies like NARP (neuropathy ataxia and 6. Cristae remodeling in apoptosis retinitis pigmentosa) or MILS (maternally inherited Leigh syndrome) [98]. The Drosophila ATP6 mutant shows a high percentage of aberrant In addition to their key role in energy metabolism, mitochondria mitochondria with a honeycomb appearance [95]. Detailed tomo- take a central position in the regulation of programmed cell death. graphic analysis revealed numerous inner membrane vesicles which They integrate numerous apoptotic stimuli and play a pivotal role in are often interconnected with each other and with the IBM. The cause the initiation of apoptosis. A central step in the mitochondrial of the perturbation of the mitochondrial inner membrane in this apoptotic pathway is the release of soluble apoptogenic proteins mutant has still to be examined. Surprisingly, in yeast a point mutation upon selective permeabilization of the outer mitochondrial mem- of the ATP6 gene resembling the NARP T8993G mutation does not brane [107,108]. Mitochondria are involved in caspase-dependent show an effect on mitochondrial ultrastructure [99] and even in the (cytochrome c, Smac/Diablo, Omi/HtrA2) as well as caspase-indepen- Δatp6 deletion strain cristae structures were observed [100], indicat- dent (AIF, endonuclease G) death pathways [109–112]. Upon apoptotic ing that the subunit 6 of the F1FO-ATP synthase is not absolutely stimuli a major caspase-activating pathway is triggered by cyto- required for the formation of cristae. Interestingly, the inner chrome c [6,113,114]. The release of cytochrome c upon permeabiliza- membrane often showed septa-like structures, but those electron tion of the outer membrane was observed to be complete [115,116], micrographs presented to underline this claim lacked any discernible although more than an estimated 85% of cytochrome c is stored in the cristae. Thus, cristae formation might in principle be possible but still intracristal space [117]. Scorrano and colleagues have shown that after appears impaired in cells lacking ATP6 consistent with aforemen- induction of apoptosis an extensive remodeling of the mitochondrial tioned results from other organisms. In addition, profound morpho- inner membrane occurs resulting in an increased accessibility of logical alterations of the mitochondrial network were observed in the cytochrome c [118]. These results led to the hypothesis that Δatp6 deletion strain, which, in conjunction with the septa-like remodeling of the CM, particularly of CJs, is a necessary step in structures, was attributed to a delayed inner membrane fusion due to apoptosis [118]. What are the molecular mechanisms that could the bioenergetic impairment [100]. The latter is consistent with earlier explain cristae remodeling and the release of cytochrome c? reports showing that [Float1]in a different ATP6 mutant the formation of the short isoform of Mgm1p is compromised resulting in impaired 7. The role of OPA1 in apoptotic cristae remodeling fusion of mitochondria [101]. Taken together, although the importance of the F1FO-ATP synthase in cristae formation is apparent, future One key player turned out to be OPA1, a large dynamin-like GTPase, studies are required in order to decipher the molecular determinants which is associated with mutations causing autosomal dominant optic for the assembly of higher oligomeric forms of this complex. atrophy type I [119,120]. OPA1 is known to be required for In this regard the determination of the three-dimensional mitochondrial fusion [121,122]. Further, downregulation of OPA1 by structure of the higher oligomeric assemblies of the F1FO-ATP RNAi resulted in ultrastructural changes of cristae and accelerated synthase is certainly highly desirable and considerable progress has release of cytochrome c upon induction of apoptosis [121]. The role of been made recently. Analysis by single particle electron microscopic OPA1 in a cristae-remodeling pathway received further support as studies revealed two different types of F1FO-ATP synthase dimers in OPA1 overexpression was anti-apoptotic and induced tightening of CJs yeast which are oriented with an angle of 35° or 90° between the long [123,124]. The latter was attributed to the capacity of OPA1 to engage axes of the F1FO-ATP synthase monomers [102]. For bovine heart [103] in homotypic interactions. Disruption of an OPA1 complex might and the colorless alga Polytomella [104] angles of about 40° and 70°, therefore explain the increased sensitivity for cristae remodeling and respectively, have been obtained. Whether the observed variation release of cytochrome c upon induction of apoptosis [123–125]. Also between these species is due to their distant evolutionary relation or Mgm1p, the yeast ortholog of OPA1, was proposed to make homotypic whether it is derived from different classes of dimers, wide-angle interactions and to be required for formation of normal amounts of dimers (70°–90°) and small-angle dimers (35°–40°), remains an open cristae structures [126]. The activity of OPA1 in mitochondrial fusion 12 M. Zick et al. / Biochimica et Biophysica Acta 1793 (2009) 5–19 M. Zick et al. / Biochimica et Biophysica Acta 1793 (2009) 5–19 13 was shown to be regulated by proteolytic processing of OPA1 disintegration of the mitochondrial inner membrane topology, [127,128]. This process causes changes of mitochondrial morphology favoring bioenergetic impairment and alleviated release of cyto- in several model systems of mitochondrial dysfunction and could chrome c to the cytosol. allow the spatial separation and removal of damaged mitochondria by Another protein with a recently discovered potential role in autophagy [127]. Recently, processing of large OPA1 isoforms was remodeling of the inner membrane is DIC-1, the C. elegans homologue shown to exert an essential function in cristae morphogenesis in a of the human DICE1 (deleted in cancer 1) [153]. DICE1 seems to process controlled by prohibitins [129]. PHB2-deficient cells exhibit a exhibit tumor suppressor function, as its downregulation has been selective loss of larger OPA1 isoforms. This goes along with an found in association with non-small cell lung cancer [154], as well as aberrant inner membrane topology and increased sensitivity towards prostate cancer [155]. The precise function however remains largely apoptotic stimuli, defects that can be suppressed by overexpression of unknown. Han et al. could show that DIC-1 is localized in the larger OPA1 isoforms. Several mitochondrial proteases have been mitochondrial inner membrane, particularly the cristae compartment, discussed to be responsible for OPA1 cleavage at different sites, where it plays an essential role in membrane organization. Knock- including PARL [123,125], the i-AAA protease Yme1L [130,131], and the down of dic-1 in C. elegans resulted in an extensive remodeling of the m-AAA protease [128,132]. As prohibitins are known to regulate inner membrane, exhibiting an aberrant mitochondrial ultrastructure protein degradation by m-AAA proteases in yeast [133] the role of the with numerous densely packed inner membrane vesicles, and an m-AAA protease appears to be of particular importance in this process. increased frequency of apoptosis [153]. The mammalian DICE1 has by Future studies, however, are needed to clarify the regulation of cristae contrast been localized to nuclei [156,157]. It has been implicated in formation by one or more of these proteases. suppression of cell proliferation [156,158] and small nuclear RNA processing [159]. Further studies are necessary to address this 8. Other candidates involved in cristae remodeling during apparent discrepancy and will eventually elucidate multiple functions apoptosis of the mammalian DICE1. Although several candidate proteins have been implicated in cristae The Bcl-2 protein family is a large group of proteins involved in the remodeling during apoptosis, the physiological relevance of this process regulation of programmed cell death by performing either pro- or was cast into doubt as, according to computer simulations, CJs might not anti-apoptotic activity [134]. Administration of tBid, a truncated form represent an insurmountable diffusion barrier in order to be consistent of the pro-apoptotic BH3-only protein Bid [135], to isolated mouse with experimental results [116,160]. This view recently found support liver mitochondria induced considerable remodeling of the mitochon- by a study which followed mitochondrial transformation during drial inner membrane and liberation of cytochrome c into the in- apoptosis using correlated three-dimensional fluorescence and electron termembrane space [118]. While the mechanism behind this microscopy [161]. A multi-step transformation of the mitochondrial phenomenon is yet not quite clear, an interaction of tBid with inner membrane was observed which temporarily exhibited a number cardiolipin preferentially at mitochondrial contact sites has been of isolated vesicular compartments surrounding the matrix and implicated in the observed cristae reorganization [136,137]. ultimately resulted in a swollen conformation with very few lamellar The interplay between mitochondria and the endoplasmatic cristae. However, the efficient release of cytochrome c occurred prior to reticulum (ER) could also play an important role in the regulation of any of these events [161]. Taken together, the role of cristae remodeling apoptosis as well [138–140]. BIK, a BH3-only protein located in the ER, in apoptosis as well as the respective components and their mode of activates transmission of Ca2+ from the ER to mitochondria, which action are still under debate. results in the recruitment of DRP1 to mitochondria and thereby appears to contribute to cristae remodeling [141] (extensively re- 8.1. Shaping the mitochondrial network is linked to cristae formation viewed in [142]). In agreement with this, Zhang et al. have reported an involvement of mitochondrial permeability transition in the remodel- A systematic genome-wide screening in yeast resulted in the ing of CJs, and thus cytochrome c release, during ER stress [143]. The identification of novel genes important for mitochondrial distribution precise mode of action underlying these processes, however, still and morphology (MDM) [162]. One of the identified proteins, Mdm33p, needs to be determined. was localized to the inner membrane and mitochondria of Mdm33p- The apoptosis-inducing factor (AIF) exhibits a dual function in devoid cells show aberrant morphology of their network as well as of cellular life and death (reviewed in [144–146]). On the one hand it their internal ultrastructure [163]. Mitochondria appear elongated and may act as the main mediator of caspase-independent apoptosis-like along extended stretches only a very narrow matrix space is visible programmed cell death [147–149] while on the other hand it may while at their tips bulky ‘handles’ are formed that contain apparently exert vital functions within mitochondria, like sustaining oxidative normal cristae structures. Overexpression of Mdm33p on the other phosphorylation by governing the integrity of the respiratory chain hand results in aggregation of mitochondria. Normal cristae are rarely complexes (mainly complex I) [150] and scavenging of reactive oxygen present, and instead, the inner membrane forms aberrant structures species [151]. In order to distinguish between these two opposing such as septa and putative vesicles [163]. Mdm33p was hence proposed functions, Cheung et al. have constructed and analyzed a mitochon- to be involved in fission of the inner mitochondrial membrane. drial inner membrane anchored form of AIF [152]. Interestingly, they Mmm1p is an integral protein of the outer membrane of yeast found AIF to be required for the maintenance of normal cristae mitochondria that affects both the overall shape and the ultrastruc- structure. Knockout of AIF led to the formation of aberrant, dilated ture of this organelle [164]. Disruption strains or temperature cristae, while the expression of anchored AIF could restore wild type sensitive mutants show defective transmission of mtDNA and the like cristae morphology [152]. Thus, AIF may have two distinct pro- formation of large spherical organelles as well as a dramatic dis- apoptotic functions. Next to the role it plays after translocation to the organization of the mitochondrial cristae compartment, including a nucleus [147–149], loss of AIF from mitochondria may lead to collapse and stack formation of the inner mitochondrial membrane

Fig. 6. Models of cristae formation and propagation. Several theoretical models for the formation of cristae (A–E) as well as a model for their propagation from existing cristae (F) are proposed. The individual steps are shown in chronological sequence from left to right for each model. (A) ‘Invagination model’ or ‘Late-crista junction model’. (B) ‘Balloon model’ or ‘Early-crista junction model’. (C) ‘De-novo vesicle germination model’. (D) ‘Fusion-remnant model’. (E) ‘Hemifusion model’. In the left panel of D an overview of the fusion event of two mitochondria is depicted. Other panels in D and E show enlargements of the indicated box. The individual leaﬂets of the mitochondrial inner membrane are illustrated in different colors (red/green) for clarity. (F) ‘Cristae ﬁssion–fusion model’. A detailed description of all proposed models can be found in the text. IMS, intermembrane space; IM, inner membrane; M, matrix. 14 M. Zick et al. / Biochimica et Biophysica Acta 1793 (2009) 5–19

[165]. A Mmm1p-GFP fusion protein was localized to distinct foci at favored structures and thus form spontaneously under certain the outer mitochondrial membrane, often in close vicinity to mtDNA conditions [180], as exemplified by their spontaneous reformation in nucleoids [165]. Mmm1p was proposed to span the mitochondrial yeast mitochondria after extensive swelling and recontraction of the outer and inner membrane [166], and to connect the mitochondrial matrix compartment [42]. Alternatively, structural proteins could be surface to the actin cytoskeleton [167]. Thus, Mmm1p might be part of involved in establishing a certain membrane curvature that is crucial a scaffold-like structure necessary for normal mitochondrial shape for the architecture of CJs. It has also been speculated that the physical [165]. Recently a new role for the Mmm1-complex (composed of connection of the outer and inner membranes at the so-called ‘contact Mmm1p, Mdm12p, and Mdm10p) in the import and assembly of beta- sites’ could play a role in the formation or stabilization of cristae [181]. barrel proteins in the outer membrane was proposed [168,169]. It will This idea, however, is lacking experimental support as contact sites be interesting to dissect the primary role of the Mmm1-complex. and cristae junctions were reported not to be co-localized [182]. Another interesting candidate protein identified in the aforemen- So far, three candidate proteins have been proposed: OPA1, tioned screen for defects in mitochondrial morphology is encoded by prohibitin, and mitofilin. The evidence assigning OPA1 an important the Mdm38 gene [162]. Its human ortholog, LETM1 (leucine zipper-, role in CJ formation has been described above. The observed effect of ER-hand-containing transmembrane protein 1), has been associated OPA1 overexpression on preventing an increase in CJ diameter upon with the Wolf–Hirschhorn syndrome (WHS), as it is encoded in the induction of apoptosis is probably the most direct evidence in this extended WHS critical region of chromosome 4p, that is often direction [123,124]. Prohibitins were reported to form large oligomeric subjected to microdeletions in WHS patients [170]. Both LETM1 and ring-like complexes with a diameter fitting well to those reported for its yeast homologue Mdm38p are highly conserved mitochondrial CJs [183]. Thus, it was proposed that the prohibitin complex due to its inner membrane proteins of eukaryotes [171]. Downregulation of the physical properties may participate in the formation of CJs [183]. homologous proteins in yeast, C. elegans and mammalian cells leads to Interestingly, as discussed above, OPA1 processing is controlled by osmotic swelling of the mitochondrial matrix. These morphological prohibitins linking these two candidates functionally [129]. changes are fully reversible upon administration of the K+/H+- John et al. have shown that downregulation of mitofilin led to ionophore nigericin [23,24,172]. Overexpression in contrast results ultrastructural disorganization of the mitochondrial inner membrane in condensation of the mitochondrial matrix and cristae swelling and an increased susceptibility to apoptosis [184]. Instead of tubular consistent with the suggested role of LETM1/Mdm38p as a K+/H+- cristae, the inner membrane forms closely packed stacks of concentric antiporter [172]. The function of LETM1/Mdm38p, however, is still sheets while at the same time CJs are not detectable. This points to an discussed, as it was also proposed to play a role in the Oxa1 in- elementary role of mitofilin in organizing cristae and CJs [184]. The dependent insertion of proteins into the inner membrane with a mammalian integral inner membrane protein mitofilin [185,186] is a critical role in the biogenesis of the respiratory chain [173]. However, very abundant mitochondrial protein [187] that forms homotypic the detailed role of this component in influencing mitochondrial interactions and is part of a high molecular weight complex [184]. ultrastructure is still open. Mass spectrometrical analysis identified mitofilin as one of the proteins significantly reduced in cortical brain samples of fetal 8.2. Cristae morphology and Parkinson's disease Down syndrome [188]. In gerbils a base substitution in a conserved domain of the mitofilin gene correlates with seizure-sensitivity [189].

Mitochondrial dysfunction and oxidative stress are believed to play Upon cold-acclimation mitofilin, together with the F1FO-ATP synthase, key roles in the pathogenesis of Parkinson's disease by promoting is upregulated in rat brown adipose tissue [190]. Further, mitofilin damage to dopaminergic neurons. A number of disease causing genes seems susceptible to dopamine induced oxidation what makes it a has been discovered in familial and sporadic forms of Parkinson's candidate for influencing mitochondrial stability in the pathogenesis disease, such as PINK1 (PTEN-induced kinase 1) and parkin [174,175]. of Parkinson's disease [191]. In a recent study, mitofilin has been co- PINK1 encodes a serine/threonine kinase localized to the intermem- purified with six proteins, of which four are known to be implicated in brane space [176]. Mutants of pink1 in Drosophila display swollen protein import into mitochondria making the authors propose a role mitochondria and fragmented cristae, while overexpression of parkin of mitofilin “in protein import related to maintenance of mitochon- rescues this phenotype [19,177]. Furthermore, downregulation of drial structure” [192]. Future analysis will have to reveal the exact role PINK1 results in depletion of cristae membranes and altered cristae of mitofilin in determining cristae morphology. morphology in human cells [18]. In addition, several recent studies In spite of all the data accumulated to date on these three have indicated a functional association of PINK1 and parkin to the candidate proteins, unfortunately, for none of them a direct role or mitochondrial fusion/fission machinery [18,178,179]. It has been specific localization to CJs has been shown yet. Further work is ne- shown, that inactivation of the mitochondrial fission component cessary to unravel the processes underlying the formation of CJs and to Drp1 aggravates the PINK1 as well as the parkin mutant phenotype in elucidate the precise molecular mechanisms of OPA1, prohibitin, Drosophila, while these mutant phenotypes are suppressed in mitofilin, and possibly other components involved. This will be es- situations where mitochondrial fission is enhanced or the fusion pecially challenging, since CJs make up only a very small proportion of activity is reduced. Therefore, it was proposed that PINK1 and parkin the mitochondrial inner membrane. act in a pathway promoting mitochondrial fission [178]. Another recent study supports this idea and suggests that PINK1 acts through 10. Theoretical models for the formation and maintenance of Fis1 and Drp1 in the regulation of mitochondrial fission [179].In cristae contrast, RNA interference mediated downregulation of PINK1 in human cells resulted in a fragmentation of the mitochondrial net- The mechanism of how cristae and CJs are formed is completely work, which could be rescued by overexpression of wild type but not unknown. Here we formulate several basic models of cristae pathogenic variants of parkin [18]. Thus, the precise role of PINK1 formation, which might stimulate further research leading towards within the regulation of mitochondrial dynamics remains unclear, as a better understanding of the underlying processes. From an intuitive well as its link to the observed changes in cristae morphology. perspective one way of cristae formation certainly is that they originate by invagination of the inner boundary membrane and sub- 9. Determining the architecture of crista junctions sequently CJs are formed (‘Invagination model’ or ‘Late-crista junction model’)(Fig. 6A). According to Renken et al., bending energy alone Little is known about the components contributing to the would be sufficient for this spontaneous invagination provided that formation of CJs. One possibility is that CJs are thermodynamically the surface of the inner membrane is increasing while the outer M. Zick et al. / Biochimica et Biophysica Acta 1793 (2009) 5–19 15 membrane “shell” remains constant [180]. Otherwise, this could be addition, evidence for the dynamics of the distribution of proteins mediated by a certain local, leaflet-specific lipid composition and/or within the inner membrane has been obtained recently [50]. certain protein complexes that affect the membrane curvature. The Furthermore, it has to be emphasized that although vesicles have latter was proposed to occur by means of the oligomerization of F1FO- been observed only rarely in electron micrographs/tomograms one ATP synthase [85,106]. certainly cannot neglect this possibility. Such vesicles are eventually Another model in which cristae originate from the IBM is the only formed transiently with a life-time that is very short in contrast ‘Balloon model’ or ‘Early-crista junction model’ (Fig. 6B). Here, initially to the life-time of cristae structures, thus being barely available for stable pre-crista junction complexes are formed as ring- or slot-like direct observations by current means. The concept of fusion and also structures in the IBM. Such a structure could then serve as an entry of fission of cristae membranes is intriguing as this would also region for the flow of lipids and proteins, thus promoting the for- provide a possibility for the propagation, in contrast or in addition to mation of new cristae by invagination of the inner membrane along the de novo formation of cristae membranes. Propagation of cristae this guidance. In this model, CJs act as preformed, well defined origins could be mediated such that cristae vesicles bud off from preexisting for the appearance of cristae whereas in the ‘invagination model’ CJs cristae and re-fuse with the inner membrane at a different site are formed later after broad infoldings of the inner membrane have within the mitochondrion (‘Cristae fission–fusion model’)(Fig. 6F). emerged. This would have fundamental consequences on the dynamic An entirely different concept of cristae formation is the origination behavior of lipids and proteins in the inner membrane as well as of cristae membranes from internal vesicles within the matrix com- of soluble components of the intermembrane space. Furthermore, partment that later get connected to the IBM by membrane fusion. this would imply that oxidative phosphorylation might be regulated Vesicles within the matrix compartment have indeed been observed in a novel way; maybe cristae-‘vesicles’ have to be considered in a in rare cases such as in mitochondria of patients with a defective certain sense as a transient pendant to the thylakoids of chloroplasts. adenine nucleotide carrier [41,193] or after extensive osmotic swelling It is obvious that the generation and exploitation of the electro- and recontraction of the matrix compartment [42]. This raises the chemical gradient across the inner membrane within a vesicle is question of how cristae vesicles could be formed in principle. One entirely different to the situation when the intracristal space is part possibility is the de novo formation of such vesicles from single of the same aqueous compartment as the cytosol (as the outer phospholipid molecules (‘De-novo vesicle germination model’)(Fig. membrane is considered to be permeable to small solutes). In this 6C). De novo formation of vesicles has been proposed in other regard, studying cristae dynamics is likely to be of high relevance to examples such as in the biogenesis of peroxisomes or autophago- bioenergetic aspects of mitochondrial physiology. This is technically somes [194,195]. difficult as studying cristae dynamics in mitochondria by static The formation of new cristae membranes could also be linked techniques such as electron microscopy is not possible. Thus, it will directly to the fusion of mitochondria. Such a link is supported by the be one of the great future challenges to further develop high- fact that Mgm1p as well as OPA1 are involved in both processes: resolution imaging techniques allowing to analyze such putative fusion of mitochondria and cristae formation [121–124,126,196].In dynamic processes in real-time. this case, cristae might be regarded as remnants of a preceding fusion Taken together, the proposed set of potential models provides a event and would imply that CJs originate at the initial site of inner theoretical framework for the understanding of cristae formation and membrane fusion (‘Fusion-remnant model’)(Fig. 6D). Initially, (pre)- propagation. The mentioned models are not mutually exclusive and CJs would be formed and, concomitant with membrane remodeling, presumably not complete either. Still, we consider it as important to expand towards the IBM where they eventually become anchored to speculate about such models of cristae formation in order to derive the outer membrane. Membrane remodeling is required as the testable hypotheses. It certainly will help to broaden our under- curvature of the inner membrane has to be inverted during the standing for the factors and mechanisms that govern the huge transition of an initial fusion region to a tubular or lamellar cristae variability of mitochondrial ultrastructures and how they are linked to structure. Another model involves the formation of a vesicle during mitochondrial bioenergetics. inner membrane fusion, assuming that fusion occurs via a hemifusion- based mechanism (‘Hemifusion model’)(Fig. 6E). Hemifusion is a Acknowledgements concept of membrane fusion that implies an intermediate state in which the initially apposed membrane leaflets are fused and mixed, We thank Drs Soledad Funes and Stéphane Duvezin-Caubet for the while the distal leaflets remain distinct [197,198]. It is currently not critical discussion of the manuscript, Drs Frank Vogel and Marek known what happens to the individual leaflets of the lipid bilayer Cyrklaff for providing electron micrographs, and Dr Werner Kühl- when two mitochondria fuse and whether this follows such a brandt for sharing data prior to publication. This work was supported mechanism. However, the principle of hemifusion is well established by the Deutsche Forschungsgemeinschaft SFB 594 project B8 (AR), the for several types of membrane fusion events, including the cell Cluster of Excellence “Macromolecular Complexes” at the Goethe invasion by enveloped viruses and vacuolar fusion [199–201]. In the University Frankfurt DFG Project EXC 115 (AR), and by the Ludwig- later case, it was proposed that fusion occurs via a certain type of Maximilians-Universtät München FöFoLe program (MZ). hemifusion with the involvement of ‘vertex rings’ resulting in the formation of luminal vesicles [202]. Nevertheless, as pointed out References above, the formation of a vesicle might be the initial step in cristae formation. [1] I.E. Scheffler, Mitochondria, Wiley-Liss, 1999. Both the ‘De-novo vesicle germination model’ and the ‘Hemifu- [2] L. Ernster, G. Schatz, Mitochondria: a historical review, J. Cell. Biol. 91 (1981) – sion model’ require that after cristae vesicles are transiently formed 227s 255s. [3] B.F. Lang, M.W. Gray, G. Burger, Mitochondrial genome evolution and the origin they fuse with the IBM. Topologically, such a fusion event is distinct of eukaryotes, Annu. Rev. Genet. 33 (1999) 351–397. from fusion between two mitochondria, as different sides of the [4] W. Neupert, J.M. Herrmann, Translocation of proteins into mitochondria, Annu. – inner membrane are apposed to each other during membrane Rev. Biochem. 76 (2007) 723 749. [5] R. Lill, U. Muhlenhoff, Iron–sulfur protein biogenesis in eukaryotes: components docking. There is no experimental evidence so far that fusion of and mechanisms, Annu. Rev. Cell. Dev. Biol. 22 (2006) 457–486. cristae membranes indeed occurs. However, a dynamic behavior of [6] X. Jiang, X. Wang, Cytochrome c-mediated apoptosis, Annu. Rev. Biochem. 73 cristae membranes was proposed by Mannella and colleagues, as (2004) 87–106. [7] D.C. Wallace, A mitochondrial paradigm of metabolic and degenerative diseases, cristae morphology rapidly changes in a reversible manner depend- aging, and cancer: a dawn for evolutionary medicine, Annu. Rev. Genet. 39 ing on the physiological conditions applied (see above) [42].In (2005) 359–407. 16 M. Zick et al. / Biochimica et Biophysica Acta 1793 (2009) 5–19

[8] A. Trifunovic, A. Wredenberg, M. Falkenberg, J.N. Spelbrink, A.T. Rovio, C.E. [41] T.G. Frey, C.A. Mannella, The internal structure of mitochondria, Trends. Biochem. Bruder, Y.M. Bohlooly, S. Gidlof, A. Oldfors, R. Wibom, J. Tornell, H.T. Jacobs, N.G. Sci. 25 (2000) 319–324. Larsson, Premature ageing in mice expressing defective mitochondrial DNA [42] C.A. Mannella, D.R. Pfeiffer, P.C. Bradshaw, I.I. Moraru, B. Slepchenko, L.M. Loew, polymerase, Nature 429 (2004) 417–423. C.E. Hsieh, K. Buttle, M. Marko, Topology of the mitochondrial inner membrane: [9] N. Rasmussen, Mitochondrial structure and the practice of cell biology in the dynamics and bioenergetic implications, IUBMB Life 52 (2001) 93–100. 1950s, J. Hist. Biol. 28 (1995) 381–429. [43] T.G. Frey, C.W. Renken, G.A. Perkins, Insight into mitochondrial structure and [10] D.W. Fawcett, Mitochondria, in: W.B. Saunders (Ed.), The Cell, Philadelphia, 1981. function from electron tomography, Biochim. Biophys. Acta 1555 (2002) [11] E.A. Munn, The Structure of Mitochondria, Academic Press, London, New York, 196–203. 1974. [44] G. Perkins, C. Renken, M.E. Martone, S.J. Young, M. Ellisman, T. Frey, Electron [12] J.P. Revel, D.W. Fawcett, C.W. Philpott, Observations on mitochondrial structure tomography of neuronal mitochondria: three-dimensional structure and angular configurations of the cristae, J. Cell. Biol. 16 (1963) 187–195. organization of cristae and membrane contacts, J. Struct. Biol. 119 (1997) [13] D. Acehan, Y. Xu, D.L. Stokes, M. Schlame, Comparison of lymphoblast 260–272. mitochondria from normal subjects and patients with Barth syndrome using [45] G.A. Perkins, M.H. Ellisman, D.A. Fox, Three-dimensional analysis of mouse rod electron microscopic tomography, Lab. Invest. 87 (2007) 40–48. and cone mitochondrial cristae architecture: bioenergetic and functional [14] S. Bione, P. D'Adamo, E. Maestrini, A.K. Gedeon, P.A. Bolhuis, D. Toniolo, A novel X- implications, Mol. Vis. 9 (2003) 60–73. linked gene, G4.5. is responsible for Barth syndrome, Nat. Genet. 12 (1996) [46] G.A. Perkins, J.Y. Song, L. Tarsa, T.J. Deerinck, M.H. Ellisman, T.G. Frey, Electron 385–389. tomography of mitochondria from brown adipocytes reveals crista junctions, [15] Y. Xu, R.I. Kelley, T.J. Blanck, M. Schlame, Remodeling of cardiolipin by J. Bioenerg. Biomembr. 30 (1998) 431–442. phospholipid transacylation, J. Biol. Chem. 278 (2003) 51380–51385. [47] D. Nicastro, A.S. Frangakis, D. Typke, W. Baumeister, Cryo-electron tomography of [16] S.J. Baloyannis, Mitochondrial alterations in Alzheimer's disease, J. Alzheimers neurospora mitochondria, J. Struct. Biol. 129 (2000) 48–56. Dis. 9 (2006) 119–126. [48] G.A. Perkins, C.W. Renken, I.J. van der Klei, M.H. Ellisman, W. Neupert, T.G. Frey, [17] M.J. Chung, Y.L. Suh, Ultrastructural changes of mitochondria in the skeletal Electron tomography of mitochondria after the arrest of protein import muscle of patients with amyotrophic lateral sclerosis, Ultrastruct. Pathol. 26 associated with Tom19 depletion, Eur. J. Cell. Biol. 80 (2001) 139– 150. (2002) 3–7. [49] G.A. Perkins, T.G. Frey, Recent structural insight into mitochondria gained by [18] N. Exner, B. Treske, D. Paquet, K. Holmstrom, C. Schiesling, S. Gispert, I. Carballo- microscopy, Micron 31 (2000) 97–111. Carbajal, D. Berg, H.H. Hoepken, T. Gasser, R. Kruger, K.F. Winklhofer, F. Vogel, A.S. [50] F. Vogel, C. Bornhövd, W. Neupert, A.S. Reichert, Dynamic subcompartmentaliza- Reichert, G. Auburger, P.J. Kahle, B. Schmid, C. Haass, Loss-of-function of human tion of the mitochondrial inner membrane, J. Cell. Biol. 175 (2006) 237–247. PINK1 results in mitochondrial pathology and can be rescued by parkin, [51] S. Werner, W. Neupert, Functional and biogenetical heterogeneity of the inner J. Neurosci. 27 (2007) 12413–12418. membrane of rat-liver mitochondria, Eur. J. Biochem. 25 (1972) 379–396. [19] I.E. Clark, M.W. Dodson, C. Jiang, J.H. Cao, J.R. Huh, J.H. Seol, S.J. Yoo, B.A. Hay, M. [52] K. Ohlendieck, I. Riesinger, V. Adams, J. Krause, D. Brdiczka, Enrichment and Guo, Drosophila pink1 is required for mitochondrial function and interacts biochemical characterization of boundary membrane contact sites from rat-liver genetically with parkin, Nature 441 (2006) 1162–1166. mitochondria, Biochim. Biophys. Acta 860 (1986) 672–689. [20] P.A. Trimmer, R.H. Swerdlow, J.K. Parks, P. Keeney, J.P. Bennett Jr., S.W. Miller, R.E. [53] L. Pon, T. Moll, D. Vestweber, B. Marshallsay, G. Schatz, Protein import into Davis, W.D. Parker Jr., Abnormal mitochondrial morphology in sporadic mitochondria: ATP-dependent protein translocation activity in a submitochon- Parkinson's and Alzheimer's disease cybrid cell lines, Exp. Neurol. 162 (2000) drial fraction enriched in membrane contact sites and specific proteins, J. Cell. 37–50. Biol. 109 (1989) 2603–2616. [21] C.C. Stichel, X.R. Zhu, V. Bader, B. Linnartz, S. Schmidt, H. Lubbert, Mono- and [54] M. Schwaiger, V. Herzog, W. Neupert, Characterization of translocation contact double-mutant mouse models of Parkinson's disease display severe mitochon- sites involved in the import of mitochondrial proteins, J. Cell. Biol. 105 (1987) drial damage, Hum. Mol. Genet. 16 (2007) 3377–3393. 235–246. [22] M.F. Beal, Mitochondria and neurodegeneration, Novartis Found. Symp. 287 [55] A.S. Reichert, W. Neupert, Contact sites between the outer and inner membrane (2007) 183–192 (discussion 192–186). of mitochondria—role in protein transport, Biochim. Biophys. Acta 1592 (2002) [23] A. Hasegawa, A.M. van der Bliek, Inverse correlation between expression of the 41. Wolfs Hirschhorn candidate gene Letm1 and mitochondrial volume in C. elegans [56] M.E. Perotti, W.A. Anderson, H. Swift, Quantitative cytochemistry of the and in mammalian cells, Hum. Mol. Genet. 16 (2007) 2061–2071. diaminobenzidine cytochrome oxidase reaction product in mitochondria of [24] K.S. Dimmer, F. Navoni, A. Casarin, E. Trevisson, S. Endele, A. Winterpacht, L. cardiac muscle and pancreas, J. Histochem. Cytochem. 31 (1983) 351–365. Salviati, L. Scorrano, LETM1, deleted in Wolf Hirschhorn syndrome is required for [57] R.W. Gilkerson, J.M. Selker, R.A. Capaldi, The cristal membrane of mitochondria is normal mitochondrial morphology and cellular viability, Hum. Mol. Genet. 17 the principal site of oxidative phosphorylation, FEBS Lett. 546 (2003) 355–358. (2008) 201–214. [58] C.A. Wurm, S. Jakobs, Differential protein distributions define two sub- [25] A.D. Bergemann, F. Cole, K. Hirschhorn, The etiology of Wolf–Hirschhorn compartments of the mitochondrial inner membrane in yeast, FEBS Lett. 580 syndrome, Trends. Genet. 21 (2005) 188–195. (2006) 5628–5634. [26] E.A. Roberts, B.H. Robinson, S. Yang, Mitochondrial structure and function in the [59] J. Demongeot, N. Glade, O. Hansen, A. Moreira, An open issue: the inner untreated Jackson toxic milk (tx-j) mouse, a model for Wilson disease, Mol. mitochondrial membrane (IMM) as a free boundary problem, Biochimie 89 Genet. Metab. 93 (2008) 54–65. (2007) 1049–1057. [27] I. Sternlieb, N. Quintana, I. Volenberg, M.L. Schilsky, An array of mitochondrial [60] P. Mitchell, Coupling of phosphorylation to electron and hydrogen transfer by a alterations in the hepatocytes of Long-Evans Cinnamon rats, Hepatology 22 chemi-osmotic type of mechanism, Nature 191 (1961) 144–148. (1995) 1782–1787. [61] W.C. Schneider, G.H. Hogeboom, Cytochemical studies of mammalian tissues; [28] C.A. Davie, A.H. Schapira, Wilson disease, Int. Rev. Neurobiol. 53 (2002) 175– 190. the isolation of cell components by differential centrifugation: a review, Cancer [29] E. Holme, J. Greter, C.E. Jacobson, N.G. Larsson, S. Lindstedt, K.O. Nilsson, A. Res. 11 (1951) 1–22. Oldfors, M. Tulinius, Mitochondrial ATP-synthase deficiency in a child with 3- [62] H. Schagger, K. Pfeiffer, Supercomplexes in the respiratory chains of yeast and methylglutaconic aciduria, Pediatr. Res. 32 (1992) 731–735. mammalian mitochondria, Embo. J. 19 (2000) 1777–1783. [30] S.M. Chou, “Megaconial” mitochondria observed in a case of chronic poly- [63] H. Eubel, J. Heinemeyer, S. Sunderhaus, H.P. Braun, Respiratory chain super- myositis, Acta. Neuropathol. 12 (1968) 68–89. complexes in plant mitochondria, Plant Physiol. Biochem. 42 (2004) 937–942. [31] G.J. van Ekeren, A.M. Stadhouders, G.J. Egberink, R.C. Sengers, O. Daniels, K. [64] F. Krause, C.Q. Scheckhuber, A. Werner, S. Rexroth, N.H. Reifschneider, N.A. Kubat, Hereditary mitochondrial hypertrophic cardiomyopathy with mitochon- Dencher, H.D. Osiewacz, Supramolecular organization of cytochrome c oxidase- drial myopathy of skeletal muscle, congenital cataract and lactic acidosis, and alternative oxidase-dependent respiratory chains in the filamentous fungus Virchows Arch. A. Pathol. Anat. Histopathol. 412 (1987) 47–52. Podospora anserina, J. Biol. Chem. 279 (2004) 26453–26461. [32] G. Palade, An electron microscope study of the mitochondrial structure, [65] I. Marques, N.A. Dencher, A. Videira, F. Krause, Supramolecular organization of J. Histochem. Cytochem. 1 (1953) 188–211. the respiratory chain in Neurospora crassa mitochondria, Eukaryot. Cell. 6 (2007) [33] G.E. Palade, The fine structure of mitochondria, Anat. Rec. 114 (1952) 427–451. 2391–2405. [34] F.S. Sjostrand, Electron microscopy of mitochondria and cytoplasmic double [66] H. Schagger, Respiratory chain supercomplexes, IUBMB Life. 52 (2001) 119–128. membranes, Nature 171 (1953) 30–32. [67] I. Wittig, R. Carrozzo, F.M. Santorelli, H. Schagger, Supercomplexes and [35] F.S. Sjostrand, The ultrastructure of cells as revealed by the electron microscope, subcomplexes of mitochondrial oxidative phosphorylation, Biochim. Biophys. Int. Rev. Cytol. 5 (1956) 455–533. Acta. 1757 (2006) 1066–1072. [36] E. Andersson-Cedergren, Ultrastructure of motor end plate and sarcoplasmic [68] H. Schagger, Respiratory chain supercomplexes of mitochondria and bacteria, components of mouse skeletal muscle fiber as revealed by three-dimensional Biochim. Biophys. Acta. 1555 (2002) 154–159. reconstructions from serial sections, J. Ultrastruct. Res. 2 (1959) 5–191. [69] E.J. Boekema, H.P. Braun, Supramolecular structure of the mitochondrial [37] C. Rouiller, Physiological and pathological changes in mitochondrial morphology, oxidative phosphorylation system, J. Biol. Chem. 282 (2007) 1–4. Int. Rev. Cytol. 9 (1960) 227–292. [70] A.J. Chicco, G.C. Sparagna, Role of cardiolipin alterations in mitochondrial [38] W.T. Daems, E. Wisse, Shape and attachment of the cristae mitochondriales in dysfunction and disease, Am. J. Physiol. Cell. Physiol. 292 (2007) C33–C44. mouse hepatic cell mitochondria, J. Ultrastruct. Res. 16 (1966) 123–140. [71] M. Schlame, M. Ren, Barth syndrome, a human disorder of cardiolipin [39] C.A. Mannella, M. Marko, P. Penczek, D. Barnard, J. Frank, The internal metabolism, FEBS. Lett. 580 (2006) 5450–5455. compartmentation of rat-liver mitochondria: tomographic study using the [72] Y. Xu, M. Condell, H. Plesken, I. Edelman-Novemsky, J. Ma, M. Ren, M. Schlame, A high-voltage transmission electron microscope, Microsc. Res. Tech. 27 (1994) Drosophila model of Barth syndrome, Proc. Natl. Acad. Sci. U. S. A. 103 (2006) 278–283. 11584–11588. [40] C.A. Mannella, M. Marko, K. Buttle, Reconsidering mitochondrial structure: new [73] K. Brandner, D.U. Mick, A.E. Frazier, R.D. Taylor, C. Meisinger, P. Rehling, Taz1, an views of an old organelle, Trends. Biochem. Sci. 22 (1997) 37–38. outer mitochondrial membrane protein, affects stability and assembly of inner M. Zick et al. / Biochimica et Biophysica Acta 1793 (2009) 5–19 17

membrane protein complexes: implications for Barth Syndrome, Mol. Biol. Cell. ATP synthase subunit 6 exhibit a selective loss of complex IV and unusual 16 (2005) 5202–5214. mitochondrial morphology, J. Biol. Chem. 282 (2007) 10853–10864. [74] M. McKenzie, M. Lazarou, D.R. Thorburn, M.T. Ryan, Mitochondrial respiratory [101] M. Herlan, C. Bornhövd, K. Hell, W. Neupert, A.S. Reichert, Alternative chain supercomplexes are destabilized in Barth Syndrome patients, J. Mol. Biol. topogenesis of Mgm1 and mitochondrial morphology depend on ATP and a 361 (2006) 462–469. functional import motor, J. Cell. Biol. 165 (2004) 167–173. [75] K. Pfeiffer, V. Gohil, R.A. Stuart, C. Hunte, U. Brandt, M.L. Greenberg, H. Schagger, [102] N.V. Dudkina, S. Sunderhaus, H.P. Braun, E.J. Boekema, Characterization of Cardiolipin stabilizes respiratory chain supercomplexes, J. Biol. Chem. 278 (2003) dimeric ATP synthase and cristae membrane ultrastructure from Saccharomyces 52873–52880. and Polytomella mitochondria, FEBS Lett. 580 (2006) 3427–3432. [76] M. Klingenberg, K. Grebe, B. Scherer, Opposite effects of bongkrekic acid and [103] F. Minauro-Sanmiguel, S. Wilkens, J.J. Garcia, Structure of dimeric mitochondrial atractyloside on the adenine nucleotides induced mitochondrial volume changes ATP synthase: novel F0 bridging features and the structural basis of mitochon- and on the efflux of adenine nucleotides, FEBS Lett. 16 (1971) 253–256. drial cristae biogenesis, Proc. Natl. Acad. Sci. U. S. A. 102 (2005) 12356–12358. [77] M. Klingenberg, B. Scherer, L. Stengel-Rutkowski, M. Buchholz, K. Grebe, [104] N.V. Dudkina, J. Heinemeyer, W. Keegstra, E.J. Boekema, H.P. Braun, Structure of Experimental demonstration of the reorienting (mobile) carrier mechanism dimeric ATP synthase from mitochondria: an angular association of monomers exemplified by the mitochondrial adenine nucleotide translocator, in: G.F. induces the strong curvature of the inner membrane, FEBS Lett. 579 (2005) Azzone, L. Ernster, S. Papa, E. Quagliariello, N. Siliprandi (Eds.), Mechanisms in 5769–5772. Bioenergetics, Academic Press, New York and London, 1973, pp. 257–284. [105] N. Buzhynskyy, P. Sens, V. Prima, J.N. Sturgis, S. Scheuring, Rows of ATP synthase [78] B. Scherer, M. Klingenberg, Demonstration of the relationship between the dimers in native mitochondrial inner membranes, Biophys. J. 93 (2007) adenine nucleotide carrier and the structural changes of mitochondria as 2870–2876. induced by adenosine 5ô-diphosphate, Biochemistry 13 (1974) 161–170. [106] M. Strauss, G. Hofhaus, R.R. Schroder, W. Kuhlbrandt, Dimer ribbons of ATP [79] C.R. Hackenbrock, Ultrastructural bases for metabolically linked mechanical synthase shape the inner mitochondrial membrane, EMBO J. 27 (2008) activity in mitochondria: I. Reversible ultrastructural changes with change in 1154–1160. metabolic steady state in isolated liver mitochondria, J. Cell. Biol. 30 (1966) [107] J.E. Chipuk, L. Bouchier-Hayes, D.R. Green, Mitochondrial outer membrane 269–297. permeabilization during apoptosis: the innocent bystander scenario, Cell. Death [80] C.R. Hackenbrock, Ultrastructural bases for metabolically linked mechanical Differ. 13 (2006) 1396–1402. activity in mitochondria: II. Electron transport-linked ultrastructural transfor- [108] D. Spierings, G. McStay, M. Saleh, C. Bender, J. Chipuk, U. Maurer, D.R. Green, mations in mitochondria, J. Cell. Biol. 37 (1968) 345–369. Connected to death: the (unexpurgated) mitochondrial pathway of apoptosis, [81] R.D. Allen, C.C. Schroeder, A.K. Fok, An investigation of mitochondrial inner Science 310 (2005) 66–67. membranes by rapid-freeze deep-etch techniques, J. Cell. Biol. 108 (1989) [109] A. Degterev, M. Boyce, J. Yuan, A decade of caspases, Oncogene 22 (2003) 2233–2240. 8543–8567. [82] R.D. Allen, Membrane tubulation and proton pumps, Protoplasma 189 (1995) [110] G. Kroemer, S.J. Martin, Caspase-independent cell death, Nat. Med. 11 (2005) 1–8. 725–730. [83] I. Arnold, K. Pfeiffer, W. Neupert, R.A. Stuart, H. Schagger, Yeast mitochondrial [111] C. Munoz-Pinedo, A. Guio-Carrion, J.C. Goldstein, P. Fitzgerald, D.D. Newmeyer, F1F0-ATP synthase exists as a dimer: identification of three dimer-specific D.R. Green, Different mitochondrial intermembrane space proteins are released subunits, Embo. J. 17 (1998) 7170–7178. during apoptosis in a manner that is coordinately initiated but can vary in [84] M.F. Giraud, P. Paumard, V. Soubannier, J. Vaillier, G. Arselin, B. Salin, J. Schaeffer, duration, Proc. Natl. Acad. Sci. U. S. A. 103 (2006) 11573–11578. D. Brethes, J.P. di Rago, J. Velours, Is there a relationship between the [112] M. van Gurp, N. Festjens, G. van Loo, X. Saelens, P. Vandenabeele, Mitochondrial supramolecular organization of the mitochondrial ATP synthase and the intermembrane proteins in cell death, Biochem. Biophys. Res. Commun. 304 formation of cristae? Biochim. Biophys. Acta 1555 (2002) 174–180. (2003) 487–497. [85] P. Paumard, J. Vaillier, B. Coulary, J. Schaeffer, V. Soubannier, D.M. Mueller, D. [113] C. Garrido, L. Galluzzi, M. Brunet, P.E. Puig, C. Didelot, G. Kroemer, Mechanisms of Brethes, J.P. di Rago, J. Velours, The ATP synthase is involved in generating cytochrome c release from mitochondria, Cell. Death Differ. 13 (2006) mitochondrial cristae morphology, Embo J. 21 (2002) 221–230. 1423–1433. [86] C. Bornhövd, F. Vogel, W. Neupert, A.S. Reichert, Mitochondrial membrane [114] X. Liu, C.N. Kim, J. Yang, R. Jemmerson, X. Wang, Induction of apoptotic program potential is dependent on the oligomeric state of F1F0-ATP synthase supracom- in cell-free extracts: requirement for dATP and cytochrome c, Cell 86 (1996) plexes, J. Biol. Chem. 281 (2006) 13990–13998. 147–157. [87] G. Arselin, J. Vaillier, B. Salin, J. Schaeffer, M.F. Giraud, A. Dautant, D. Brethes, J. [115] J.C. Goldstein, C. Munoz-Pinedo, J.E. Ricci, S.R. Adams, A. Kelekar, M. Schuler, R.Y. Velours, The modulation in subunits e and g amounts of yeast ATP synthase Tsien, D.R. Green, Cytochrome c is released in a single step during apoptosis, Cell. modifies mitochondrial cristae morphology, J. Biol. Chem. 279 (2004) Death Differ. 12 (2005) 453–462. 40392–40399. [116] J.C. Goldstein, N.J. Waterhouse, P. Juin, G.I. Evan, D.R. Green, The coordinate [88] V. Soubannier, J. Vaillier, P. Paumard, B. Coulary, J. Schaeffer, J. Velours, In the release of cytochrome c during apoptosis is rapid, complete and kinetically absence of the first membrane-spanning segment of subunit 4(b), the yeast ATP invariant, Nat. Cell. Biol. 2 (2000) 156–162. synthase is functional but does not dimerize or oligomerize, J. Biol. Chem. 277 [117] P. Bernardi, G.F. Azzone, Cytochrome c as an electron shuttle between the outer (2002) 10739–10745. and inner mitochondrial membranes, J. Biol. Chem. 256 (1981) 7187–7192. [89] T. Weimann, J. Vaillier, B. Salin, J. Velours, The intermembrane space loop of [118] L. Scorrano, M. Ashiya, K. Buttle, S. Weiler, S.A. Oakes, C.A. Mannella, S.J. subunit b (4) is a major determinant of the stability of yeast oligomeric ATP Korsmeyer, A distinct pathway remodels mitochondrial cristae and mobilizes synthases, Biochemistry 47 (2008) 3556–3563. cytochrome c during apoptosis, Dev. Cell. 2 (2002) 55–67. [90] P.D. Gavin, M. Prescott, S.E. Luff, R.J. Devenish, Cross-linking ATP synthase [119] C. Alexander, M. Votruba, U.E. Pesch, D.L. Thiselton, S. Mayer, A. Moore, M. complexes in vivo eliminates mitochondrial cristae, J. Cell. Sci. 117 (2004) Rodriguez, U. Kellner, B. Leo-Kottler, G. Auburger, S.S. Bhattacharya, B. Wissinger, 2333–2343. OPA1, encoding a dynamin-related GTPase, is mutated in autosomal dominant [91] P.D. Gavin, M. Prescott, R.J. Devenish, F1F0-ATP synthase complex interactions in optic atrophy linked to chromosome 3q28, Nat. Genet. 26 (2000) 211–215. vivo can occur in the absence of the dimer specific subunit e, J. Bioenerg. [120] C. Delettre, G. Lenaers, J.M. Griffoin, N. Gigarel, C. Lorenzo, P. Belenguer, L. Biomembr. 37 (2005) 55–66. Pelloquin, J. Grosgeorge, C. Turc-Carel, E. Perret, C. Astarie-Dequeker, L. [92] R. Fronzes, T. Weimann, J. Vaillier, J. Velours, D. Brethes, The peripheral stalk Lasquellec, B. Arnaud, B. Ducommun, J. Kaplan, C.P. Hamel, Nuclear gene OPA1, participates in the yeast ATP synthase dimerization independently of e and g encoding a mitochondrial dynamin-related protein, is mutated in dominant subunits, Biochemistry 45 (2006) 6715–6723. optic atrophy, Nat. Genet. 26 (2000) 207–210. [93] V. Goyon, R. Fronzes, B. Salin, J.-P. di Rago, J. Velours, D. Brethes, Yeast cells [121] A. Olichon, L. Baricault, N. Gas, E. Guillou, A. Valette, P. Belenguer, G. Lenaers, Loss depleted in Atp14p fail to assemble Atp6p within the ATP synthase and exhibit of OPA1 perturbates the mitochondrial inner membrane structure and integrity, altered mitochondrial cristae morphology, J. Biol. Chem. 283 (2008) 9749–9758. leading to cytochrome c release and apoptosis, J. Biol. Chem. 278 (2003) [94] I. Wittig, J. Velours, R. Stuart, H. Schagger, Characterization of domain-interfaces 7743–7746. in monomeric and dimeric ATP synthase, Mol. Cell. Proteomics (2008) 995–1004. [122] S. Cipolat, O.M. de Brito, B. Dal Zilio, L. Scorrano, OPA1 requires mitofusin 1 to [95] A.M. Celotto, A.C. Frank, S.W. McGrath, T. Fergestad, W.A. Van Voorhies, K.F. promote mitochondrial fusion, Proc. Natl. Acad. Sci. U. S. A. 101 (2004) Buttle, C.A. Mannella, M.J. Palladino, Mitochondrial encephalomyopathy in Dro- 15927–15932. sophila, J. Neurosci. 26 (2006) 810–820. [123] S. Cipolat, T. Rudka, D. Hartmann, V. Costa, L. Serneels, K. Craessaerts, K. Metzger, [96] P.D. Boyer, The ATP synthase—a splendid molecular machine, Annu. Rev. C. Frezza, W. Annaert, L. D'Adamio, C. Derks, T. Dejaegere, L. Pellegrini, R. Biochem. 66 (1997) 717–749. D'Hooge, L. Scorrano, B. De Strooper, Mitochondrial rhomboid PARL regulates [97] R.J. Devenish, M. Prescott, X. Roucou, P. Nagley, Insights into ATP synthase cytochrome c release during apoptosis via OPA1-dependent cristae remodeling, assembly and function through the molecular genetic manipulation of subunits Cell 126 (2006) 163–175. of the yeast mitochondrial enzyme complex, Biochim. Biophys. Acta.1458 (2000) [124] C. Frezza, S. Cipolat, O. Martins de Brito, M. Micaroni, G.V. Beznoussenko, T. 428–442. Rudka, D. Bartoli, R.S. Polishuck, N.N. Danial, B. De Strooper, L. Scorrano, OPA1 [98] E.A. Schon, S. Santra, F. Pallotti, M.E. Girvin, Pathogenesis of primary defects in controls apoptotic cristae remodeling independently from mitochondrial fusion, mitochondrial ATP synthesis, Semin. Cell. Dev. Biol. 12 (2001) 441–448. Cell 126 (2006) 177–189. [99] M. Rak, E. Tetaud, S. Duvezin-Caubet, N. Ezkurdia, M. Bietenhader, J. Rytka, J.P. [125] L. Pellegrini, L. Scorrano, A cut short to death: Parl and Opa1 in the regulation of di Rago, A yeast model of the neurogenic ataxia retinitis pigmentosa (NARP) mitochondrial morphology and apoptosis, Cell. Death Differ. 14 (2007) T8993G mutation in the mitochondrial ATP synthase-6 gene, J. Biol. Chem. 282 1275–1284. (2007) 34039–34047. [126] S. Meeusen, R. DeVay, J. Block, A. Cassidy-Stone, S. Wayson, J.M. McCaffery, J. [100] M. Rak, E. Tetaud, F. Godard, I. Sagot, B. Salin, S. Duvezin-Caubet, P.P. Slonimski, Nunnari, Mitochondrial inner-membrane fusion and crista maintenance requires J. Rytka, J.P. di Rago, Yeast cells lacking the mitochondrial gene encoding the the dynamin-related GTPase Mgm1, Cell 127 (2006) 383–395. 18 M. Zick et al. / Biochimica et Biophysica Acta 1793 (2009) 5–19

[127] S. Duvezin-Caubet, R. Jagasia, J. Wagener, S. Hofmann, A. Trifunovic, A. Hansson, [155] A. Ropke, P. Buhtz, M. Bohm, J. Seger, I. Wieland, E.P. Allhoff, P.F. Wieacker, A. Chomyn, M.F. Bauer, G. Attardi, N.G. Larsson, W. Neupert, A.S. Reichert, Promoter CpG hypermethylation and downregulation of DICE1 expression in Proteolytic processing of OPA1 links mitochondrial dysfunction to alterations in prostate cancer, Oncogene 24 (2005) 6667–6675. mitochondrial morphology, J. Biol. Chem. 281 (2006) 37972–37979. [156] H.B. Hoff III, M. Tresini, S. Li, C. Sell, DBI-1, a novel gene related to the notch [128] N. Ishihara, Y. Fujita, T. Oka, K. Mihara, Regulation of mitochondrial morphology family, modulates mitogenic response to insulin-like growth factor 1, Exp. Cell. through proteolytic cleavage of OPA1, Embo J. 25 (2006) 2966–2977. Res. 238 (1998) 359–370. [129] C. Merkwirth, S. Dargazanli, T. Tatsuta, S. Geimer, B. Lower, F.T. Wunderlich, J.C. [157] I. Wieland, A. Ropke, M. Stumm, C. Sell, U.H. Weidle, P.F. Wieacker, Molecular von Kleist-Retzow, A. Waisman, B. Westermann, T. Langer, Prohibitins control characterization of the DICE1 (DDX26) tumor suppressor gene in lung carcinoma cell proliferation and apoptosis by regulating OPA1-dependent cristae morpho- cells, Oncol. Res. 12 (2001) 491–500. genesis in mitochondria, Genes Dev. 22 (2008) 476–488. [158] I. Wieland, C. Sell, U.H. Weidle, P. Wieacker, Ectopic expression of DICE1 [130] L. Griparic, T. Kanazawa, A.M. van der Bliek, Regulation of the mitochondrial suppresses tumor cell growth, Oncol. Rep. 12 (2004) 207–211. dynamin-like protein Opa1 by proteolytic cleavage, J. Cell. Biol. 178 (2007) [159] D. Baillat, M.A. Hakimi, A.M. Naar, A. Shilatifard, N. Cooch, R. Shiekhattar, 757–764. Integrator, a multiprotein mediator of small nuclear RNA processing, associates [131] Z. Song, H. Chen, M. Fiket, C. Alexander, D.C. Chan, OPA1 processing controls with the C-terminal repeat of RNA polymerase II, Cell 123 (2005) 265–276. mitochondrial fusion and is regulated by mRNA splicing, membrane potential, [160] J.C. Manor, P. Salamon, J. Nulton, J.M. Mahaffy, A.R. Baljon, T.G. Frey, Membrane and Yme1L, J. Cell. Biol. 178 (2007) 749–755. remodeling and diffusion of cytochrome c from a geometrically idealized [132] S. Duvezin-Caubet, M. Koppen, J. Wagener, M. Zick, L. Israel, A. Bernacchia, R. mitochondrial crista, in: H.R. Arabnia, H. Valafar (Eds.), The 2006 International Jagasia, E.I. Rugarli, A. Imhof, W. Neupert, T. Langer, A.S. Reichert, OPA1 Conference on Bioinformatics & Computational Biology, CSREA Press, Las Vegas, processing reconstituted in yeast depends on the subunit composition of the USA, 2006, pp. 310–314. m-AAA protease in mitochondria, Mol. Biol. Cell. 18 (2007) 3582–3590. [161] M.G. Sun, J. Williams, C. Munoz-Pinedo, G.A. Perkins, J.M. Brown, M.H. Ellisman, [133] G. Steglich, W. Neupert, T. Langer, Prohibitins regulate membrane protein D.R. Green, T.G. Frey, Correlated three-dimensional light and electron microscopy degradation by the m-AAA protease in mitochondria, Mol. Cell. Biol. 19 (1999) reveals transformation of mitochondria during apoptosis, Nat. Cell. Biol. 9 (2007) 3435–3442. 1057–1072. [134] R.J. Youle, A. Strasser, The BCL-2 protein family: opposing activities that mediate [162] K.S. Dimmer, S. Fritz, F. Fuchs, M. Messerschmitt, N. Weinbach, W. Neupert, B. cell death, Nat. Rev. Mol. Cell. Biol. 9 (2008) 47–59. Westermann, Genetic basis of mitochondrial function and morphology in Sac- [135] H. Li, H. Zhu, C.J. Xu, J. Yuan, Cleavage of BID by caspase 8 mediates the charomyces cerevisiae, Mol. Biol. Cell. 13 (2002) 847–853. mitochondrial damage in the Fas pathway of apoptosis, Cell 94 (1998) 491–501. [163] M. Messerschmitt, S. Jakobs, F. Vogel, S. Fritz, K.S. Dimmer, W. Neupert, B. [136] T.H. Kim, Y. Zhao, W.X. Ding, J.N. Shin, X. He, Y.W. Seo, J. Chen, H. Rabinowich, A.A. Westermann, The inner membrane protein Mdm33 controls mitochondrial Amoscato, X.M. Yin, Bid-cardiolipin interaction at mitochondrial contact site morphology in yeast, J. Cell. Biol. 160 (2003) 553–564. contributes to mitochondrial cristae reorganization and cytochrome C release, [164] S.M. Burgess, M. Delannoy, R.E. Jensen, MMM1 encodes a mitochondrial outer Mol. Biol. Cell. 15 (2004) 3061–3072. membrane protein essential for establishing and maintaining the structure of [137] V.A. Tyurin, Y.Y. Tyurina, A.N. Osipov, N.A. Belikova, L.V. Basova, A.A. Kapralov, H. yeast mitochondria, J. Cell. Biol. 126 (1994) 1375–1391. Bayir, V.E. Kagan, Interactions of cardiolipin and lyso-cardiolipins with [165] A.E. Hobbs, M. Srinivasan, J.M. McCaffery, R.E. Jensen, Mmm1p, a mitochondrial cytochrome c and tBid: conflict or assistance in apoptosis, Cell. Death Differ. 14 outer membrane protein, is connected to mitochondrial DNA (mtDNA) nucleoids (2007) 872–875. and required for mtDNA stability, J. Cell. Biol. 152 (2001) 401–410. [138] G. Hajnoczky, G. Csordas, S. Das, C. Garcia-Perez, M. Saotome, S. Sinha Roy, M. Yi, [166] N. Kondo-Okamoto, J.M. Shaw, K. Okamoto, Mmm1p spans both the outer and Mitochondrial calcium signalling and cell death: approaches for assessing the inner mitochondrial membranes, and contains distinct domains for targeting role of mitochondrial Ca2+ uptake in apoptosis, Cell. Calcium. 40 (2006) and foci formation, J. Biol. Chem. 278 (2003) 48997–49005. 553–560. [167] I. Boldogh, N. Vojtov, S. Karmon, L.A. Pon, Interaction between mitochondria and [139] P. Pinton, R. Rizzuto, Bcl-2 and Ca2+ homeostasis in the endoplasmic reticulum, the actin cytoskeleton in budding yeast requires two integral mitochondrial Cell. Death Differ. 13 (2006) 1409–1418. outer membrane proteins, Mmm1p and Mdm10p, J. Cell. Biol. 141 (1998) [140] P. Pizzo, T. Pozzan, Mitochondria-endoplasmic reticulum choreography: struc- 1371–1381. ture and signaling dynamics, Trends. Cell. Biol. 17 (2007) 511–517. [168] C.Meisinger,M.Rissler,A.Chacinska,L.K.Szklarz,D.Milenkovic,V.Kozjak,B. [141] M. Germain, J.P. Mathai, H.M. McBride, G.C. Shore, Endoplasmic reticulum BIK Schonfisch,C.Lohaus,H.E.Meyer,M.P.Yaffe,B.Guiard,N.Wiedemann,N. initiates DRP1-regulated remodelling of mitochondrial cristae during apoptosis, Pfanner, The mitochondrial morphology protein Mdm10 functions in Embo J. 24 (2005) 1546–1556. assembly of the preprotein translocase of the outer membrane, Dev. Cell. 7 [142] H.M. Heath-Engel, G.C. Shore, Mitochondrial membrane dynamics, cristae (2004) 61–71. remodelling and apoptosis, Biochim. Biophys. Acta 1763 (2006) 549–560. [169] C. Meisinger, S. Pfannschmidt, M. Rissler, D. Milenkovic, T. Becker, D. Stojanovski, [143] D. Zhang, C. Lu, M. Whiteman, B. Chance, J.S. Armstrong, The mitochondrial M.J. Youngman, R.E. Jensen, A. Chacinska, B. Guiard, N. Pfanner, N. Wiedemann, permeability transition regulates cytochrome c release for apoptosis during The morphology proteins Mdm12/Mmm1 function in the major beta-barrel endoplasmic reticulum stress by remodeling the cristae junction, J. Biol. Chem. assembly pathway of mitochondria, EMBO J. 26 (2007) 2229–2239. 283 (2008) 3476–3486. [170] M. Zollino, R. Lecce, R. Fischetto, M. Murdolo, F. Faravelli, A. Selicorni, C. Butte, L. [144] S. Krantic, N. Mechawar, S. Reix, R. Quirion, Apoptosis-inducing factor: a matter Memo,G.Capovilla,G.Neri,MappingtheWolf–Hirschhorn syndrome of neuron life and death, Prog. Neurobiol. 81 (2007) 179–196. phenotype outside the currently accepted WHS critical region and defining a [145] N. Modjtahedi, F. Giordanetto, F. Madeo, G. Kroemer, Apoptosis-inducing factor: new critical region, WHSCR-2, Am. J. Hum. Genet. 72 (2003) 590–597. vital and lethal, Trends. Cell. Biol. 16 (2006) 264–272. [171] S. Schlickum, A. Moghekar, J.C. Simpson, C. Steglich, R.J. O'Brien, A. [146] A.G. Porter, A.G. Urbano, Does apoptosis-inducing factor (AIF) have both life and Winterpacht, S.U. Endele, LETM1, a gene deleted in Wolf–Hirschhorn death functions in cells? Bioessays 28 (2006) 834–843. syndrome, encodes an evolutionarily conserved mitochondrial protein, [147] V.L. Dawson, T.M. Dawson, Deadly conversations: nuclear–mitochondrial cross- Genomics 83 (2004) 254–261. talk, J. Bioenerg. Biomembr. 36 (2004) 287–294. [172] K. Nowikovsky, S. Reipert, R.J. Devenish, R.J. Schweyen, Mdm38 protein depletion [148]S.A.Susin,H.K.Lorenzo,N.Zamzami,I.Marzo,B.E.Snow,G.M.Brothers, causes loss of mitochondrial K+/H+ exchange activity, osmotic swelling and J. Mangion, E. Jacotot, P. Costantini, M. Loeffler, N. Larochette, D.R. Goodlett, mitophagy, Cell. Death Differ. 14 (2007) 1647–1656. R. Aebersold, D.P. Siderovski, J.M. Penninger, G. Kroemer, Molecular character- [173] A.E. Frazier, R.D. Taylor, D.U. Mick, B. Warscheid, N. Stoepel, H.E. Meyer, M.T. Ryan, ization of mitochondrial apoptosis-inducing factor, Nature 397 (1999) 441–446. B. Guiard, P. Rehling, Mdm38 interacts with ribosomes and is a component of the [149] S.W. Yu, H. Wang, M.F. Poitras, C. Coombs, W.J. Bowers, H.J. Federoff, G.G. Poirier, mitochondrial protein export machinery, J. Cell. Biol. 172 (2006) 553–564. T.M. Dawson, V.L. Dawson, Mediation of poly(ADP-ribose) polymerase-1- [174] E.M. Valente, P.M. Abou-Sleiman, V. Caputo, M.M. Muqit, K. Harvey, S. Gispert, Z. dependent cell death by apoptosis-inducing factor, Science 297 (2002) 259–263. Ali, D. Del Turco, A.R. Bentivoglio, D.G. Healy, A. Albanese, R. Nussbaum, R. [150]N.Vahsen,C.Cande,J.J.Briere,P.Benit,N.Joza,N.Larochette,P.G. Gonzalez-Maldonado, T. Deller, S. Salvi, P. Cortelli, W.P. Gilks, D.S. Latchman, R.J. Mastroberardino, M.O. Pequignot, N. Casares, V. Lazar, O. Feraud, N. Debili, S. Harvey, B. Dallapiccola, G. Auburger, N.W. Wood, Hereditary early-onset Wissing, S. Engelhardt, F. Madeo, M. Piacentini, J.M. Penninger, H. Schagger, P. Parkinson's disease caused by mutations in PINK1, Science 304 (2004) Rustin, G. Kroemer, AIF deficiency compromises oxidative phosphorylation, 1158–1160. Embo J. 23 (2004) 4679–4689. [175] T. Kitada, S. Asakawa, N. Hattori, H. Matsumine, Y. Yamamura, S. Minoshima, M. [151] J.A. Klein, C.M. Longo-Guess, M.P. Rossmann, K.L. Seburn, R.E. Hurd, W.N. Frankel, Yokochi, Y. Mizuno, N. Shimizu, Mutations in the parkin gene cause autosomal R.T. Bronson, S.L. Ackerman, The harlequin mouse mutation downregulates recessive juvenile parkinsonism, Nature 392 (1998) 605–608. apoptosis-inducing factor, Nature 419 (2002) 367–374. [176] L. Silvestri, V. Caputo, E. Bellacchio, L. Atorino, B. Dallapiccola, E.M. Valente, G. [152] E.C. Cheung, N. Joza, N.A. Steenaart, K.A. McClellan, M. Neuspiel, S. McNamara, J. Casari, Mitochondrial import and enzymatic activity of PINK1 mutants G. MacLaurin, P. Rippstein, D.S. Park, G.C. Shore, H.M. McBride, J.M. Penninger, R. associated to recessive parkinsonism, Hum. Mol. Genet. 14 (2005) 3477–3492. S. Slack, Dissociating the dual roles of apoptosis-inducing factor in maintaining [177] J. Park, S.B. Lee, S. Lee, Y. Kim, S. Song, S. Kim, E. Bae, J. Kim, M. Shong, J.M. Kim, mitochondrial structure and apoptosis, Embo J. 25 (2006) 4061–4073. J. Chung, Mitochondrial dysfunction in Drosophila PINK1 mutants is com- [153] S.M. Han, T.H. Lee, J.Y. Mun, M.J. Kim, E.A. Kritikou, S.J. Lee, S.S. Han, M.O. plemented by parkin, Nature 441 (2006) 1157–1161. Hengartner, H.S. Koo, Deleted in cancer 1 (DICE1) is an essential protein [178] A.C. Poole, R.E. Thomas, L.A. Andrews, H.M. McBride, A.J. Whitworth, L.J. Pallanck, controlling the topology of the inner mitochondrial membrane in C. elegans, The PINK1/Parkin pathway regulates mitochondrial morphology, Proc. Natl. Development 133 (2006) 3597–3606. Acad. Sci. U. S. A. 105 (2008) 1638–1643. [154] I. Wieland, K.C. Arden, D. Michels, L. Klein-Hitpass, M. Bohm, C.S. Viars, U.H. [179] Y. Yang, Y. Ouyang, L. Yang, M.F. Beal, A. McQuibban, H. Vogel, B. Lu, Pink1 Weidle, Isolation of DICE1: a gene frequently affected by LOH and downregulated regulates mitochondrial dynamics through interaction with the fission/fusion in lung carcinomas, Oncogene 18 (1999) 4530–4537. machinery, Proc. Natl. Acad. Sci. U. S. A. 105 (2008) 7070–7075. M. Zick et al. / Biochimica et Biophysica Acta 1793 (2009) 5–19 19

[180] C. Renken, G. Siragusa, G. Perkins, L. Washington, J. Nulton, P. Salamon, T.G. Frey, [192] J. Xie, M.F. Marusich, P. Souda, J. Whitelegge, R.A. Capaldi, The mitochondrial A thermodynamic model describing the nature of the crista junction: a structural inner membrane protein mitofilin exists as a complex with SAM50, metaxins 1 motif in the mitochondrion, J. Struct. Biol. 138 (2002) 137–144. and 2, coiled-coil-helix coiled-coil-helix domain-containing protein 3 and 6 and [181] I.J. van der Klei, M. Veenhuis, W. Neupert, A morphological view on DnaJC11, FEBS Lett. 581 (2007) 3545–3549. mitochondrial protein targeting, Microsc. Res. Tech. 27 (1994) 284–293. [193] M. Huizing, Mitochondrial transmembrane carriers in mitochondriocytopathies, [182] G. Perkins, C. Renken, M.E. Martone, S.J. Young, M. Ellisman, T. Frey, Electron PhD thesis, University of Nijmegen, 1998. tomography of neuronal mitochondria: three-dimensional structure and organiza- [194] P.E. Purdue, P.B. Lazarow, Peroxisome biogenesis, Annu. Rev. Cell. Dev. Biol. 17 tion of cristae and membrane contacts, J. Struct. Biol. 119 (1997) 260–272. (2001) 701–752. [183] T. Tatsuta, K. Model, T. Langer, Formation of membrane-bound ring complexes by [195] F. Reggiori, 1. Membrane origin for autophagy, Curr. Top. Dev. Biol. 74 (2006) prohibitins in mitochondria, Mol. Biol. Cell. 16 (2005) 248–259. 1–30. [184] G.B. John, Y. Shang, L. Li, C. Renken, C.A. Mannella, J.M. Selker, L. Rangell, M.J. [196] E.D. Wong, J.A. Wagner, S.W. Gorsich, J.M. McCaffery, J.M. Shaw, J. Nunnari, The Bennett, J. Zha, The mitochondrial inner membrane protein mitofilin controls dynamin-related GTPase, Mgm1p, is an intermembrane space protein required for cristae morphology, Mol. Biol. Cell. 16 (2005) 1543–1554. maintenance of fusion competent mitochondria, J. Cell. Biol. 151 (2000) 341–352. [185] C. Gieffers, F. Korioth, P. Heimann, C. Ungermann, J. Frey, Mitofilin is a [197] L.V. Chernomordik, M.M. Kozlov, Membrane hemifusion: crossing a chasm in transmembrane protein of the inner mitochondrial membrane expressed as two leaps, Cell 123 (2005) 375–382. two isoforms, Exp. Cell. Res. 232 (1997) 395–399. [198] L.V. Chernomordik, J. Zimmerberg, M.M. Kozlov, Membranes of the world unite! [186] P.R. Odgren, G. Toukatly, P.L. Bangs, R. Gilmore, E.G. Fey, Molecular characteriza- J. Cell. Biol. 175 (2006) 201–207. tion of mitofilin (HMP), a mitochondria-associated protein with predicted coiled [199] Y.A. Chizmadzhev, The mechanisms of lipid–protein rearrangements during coil and intermembrane space targeting domains, J. Cell. Sci. 109 (Pt 9) (1996) viral infection, Bioelectrochemistry (Amsterdam, Netherlands) 63 (2004) 2253–2264. 129–136. [187] S.W. Taylor, E. Fahy, B. Zhang, G.M. Glenn, D.E. Warnock, S. Wiley, A.N. Murphy, [200] J.R. Monck, J.M. Fernandez, The fusion pore and mechanisms of biological S.P. Gaucher, R.A. Capaldi, B.W. Gibson, S.S. Ghosh, Characterization of the membrane fusion, Curr. Opin. Cell. Biol. 8 (1996) 524–533. human heart mitochondrial proteome, Nat. Biotechnol. 21 (2003) 281–286. [201] C. Reese, F. Heise, A. Mayer, Trans-SNARE pairing can precede a hemifusion [188] J.K. Myung, T. Gulesserian, M. Fountoulakis, G. Lubec, Deranged hypothetical intermediate in intracellular membrane fusion, Nature 436 (2005) 410–414. proteins Rik protein, Nit protein 2 and mitochondrial inner membrane protein, [202] Y. Jun, W. Wickner, Assays of vacuole fusion resolve the stages of docking, lipid mitofilin, in fetal Down syndrome brain, Cell. Mol. Biol. (Noisy-le-grand) 49 mixing, and content mixing, Proc. Natl. Acad. Sci. U. S. A. 104 (2007) (2003) 739–746. 13010–13015. [189] A. Omori, S. Ichinose, S. Kitajima, K.W. Shimotohno, Y.L. Murashima, K. [203] T.D. Pollard, W.C. Earnshaw, Cell Biology,1st ed., Elsevier-Saunders, Philadelpihia, Shimotohno, A. Seto-Ohshima, Gerbils of a seizure-sensitive strain have a 2002. mitochondrial inner membrane protein with different isoelectric points from [204] K. Kasashima, M. Sumitani, M. Satoh, H. Endo, Human prohibitin 1 maintains the those of a seizure-resistant strain, Electrophoresis 23 (2002) 4167–4174. organization and stability of the mitochondrial nucleoids, Exp. Cell. Res. 314 [190] R. Navet, G. Mathy, P. Douette, R.L. Dobson, P. Leprince, E. De Pauw, C. Sluse- (2008) 988–996. Goffart, F.E. Sluse, Mitoproteome plasticity of rat brown adipocytes in response [205] S. Mishra, L.C. Murphy, L.J. Murphy, The prohibitins: emerging roles in diverse to cold acclimation, J. Proteome. Res. 6 (2007) 25–33. functions, J. Cell. Mol. Med. 10 (2006) 353–363. [191] V.S. Van Laar, A.A. Dukes, M. Cascio, T.G. Hastings, Proteomic analysis of rat brain [206] L.G. Nijtmans, S.M. Artal, L.A. Grivell, P.J. Coates, The mitochondrial PHB complex: mitochondria following exposure to dopamine quinone: implications for roles in mitochondrial respiratory complex assembly, ageing and degenerative Parkinson disease, Neurobiol. dis. 29 (2008) 477–489. disease, Cell. Mol. Life Sci. 59 (2002) 143–155.