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Biochimica et Biophysica Acta 1833 (2013) 381–387

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Biochimica et Biophysica Acta

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Review Protein quality control in organelles — AAA/FtsH story☆

Hanna Janska a,⁎, Malgorzata Kwasniak a, Joanna Szczepanowska b

a Department of Biotechnology, University of Wroclaw, Przybyszewskiego 63/77, 51-148 Wroclaw, Poland b Department of Biochemistry, Nencki Institute of Experimental Biology, Pasteura 3, 02-093 Warsaw, Poland

article info abstract

Article history: This review focuses on organellar AAA/FtsH , whose proteolytic and chaperone-like activity is a Received 8 February 2012 crucial component of the protein quality control systems of mitochondrial and chloroplast membranes. We Received in revised form 26 March 2012 compare the AAA/FtsH proteases from yeast, mammals and plants. The nature of the complexes formed by Accepted 27 March 2012 AAA/FtsH proteases and the current view on their involvement in degradation of non-native organellar Available online 4 April 2012 proteins or assembly of membrane complexes are discussed. Additional functions of AAA proteases not directly connected with protein quality control found in yeast and mammals but not yet in plants are also Keywords: AAA described shortly. Following an overview of the molecular functions of the AAA/FtsH proteases we discuss FtsH physiological consequences of their inactivation in yeast, mammals and plants. The molecular basis of Mitochondrion phenotypes associated with inactivation of the AAA/FtsH proteases is not fully understood yet, with the Chloroplast notable exception of those observed in m-AAA protease-deficient yeast cells, which are caused by impaired Protein quality control maturation of mitochondrial ribosomal protein. Finally, examples of cytosolic events affecting protein quality control in mitochondria and chloroplasts are given. This article is part of a Special Issue entitled: Protein Import and Quality Control in Mitochondria and Plastids. © 2012 Elsevier B.V. All rights reserved.

1. Introduction temperature sensitive H). Based on a literature search it becomes apparent that the term AAA proteases is preferentially used for the The fate of cellular proteins is dependent on the quality control mitochondrial while FtsH for the bacterial and chloroplast system necessary to prevent the accumulation of unwanted proteins ones. Most bacteria have a single gene encoding FtsH [1], three genes due to genetic mutations, biosynthetic errors, imbalanced subunit syn- are present in yeast and humans [2], while 12 orthologs are found in thesis and different types of damage caused by stress conditions. It is the genome of the model higher plant Arabidopsis thaliana [3]. The evident that the accumulation of non-native proteins can disturb multiplication of FtsH genes in higher plants is caused mainly by proteostasis leading to dysfunctional organelles and subsequently chloroplast-targeted isozymes. Out of the 12 FtsH genes in A. thaliana, reduced cellular viability. In most subcellular compartments, specific products of three have been found in mitochondria [4,5], eight can protein quality control systems comprising of molecular chaperones enter the chloroplast [6], while the product of one, FtsH11, has been and proteases have been identified. This review focuses on the AAA/FtsH reported in both mitochondria and chloroplasts [4]. proteases, enzymes with proteolytic and chaperone-like activities, as a The FtsH proteases are highly conserved, with at least 40% main element of the protein quality control systems of mitochondrial sequence identity for the E. coli, Saccharomyces cerevisiae, Homo sapiens and chloroplast membranes. and A. thaliana enzymes. All FtsH proteases have three functional domains residing on a single polypeptide chain [7,8]. The N-terminal 2. Basic characteristics of AAA/FtsH proteases transmembrane domain anchoring the in the membrane is followed by an ATPase domain of the AAA superfamily and a C-terminal AAA proteases, so named because they are members of the AAA M41 metallopeptidase domain. The ATPase domain also called the AAA superfamily (“Triple A” ATPases Associated with diverse cellular domain/cassette is believed to act as a molecular chaperone [9] and Activities), are ATP-dependent metallopeptidases present in eubac- contains characteristic motifs important for ATP binding (Walker A) teria as well as in organelles of bacterial origin, i.e., mitochondria and ATP hydrolysis (Walker B, second region of homology). The M41 and chloroplasts. The AAA proteases are also termed FtsH and this metallopeptidase domain harbors the protease active center with the label refers to the name of an Escherichia coli enzyme (Filamentous metal-binding motif HEXXH characteristic for Zn-dependent metallo- proteases. Apart from the two histidine residues of the HEXXH motif, FtsHs contain a third zinc ligand (asparatic acid) and therefore belong to ☆ This article is part of a Special Issue entitled: Protein Import and Quality Control in the subclass called “Asp-zincins” [10]. The presence of one or two Mitochondria and Plastids. ⁎ Corresponding author. Tel.: +48 71 3756249; fax: +48 71 3756234. transmembrane regions results in two different topologies of the AAA E-mail address: [email protected] (H. Janska). proteases in the respective membrane. The E. coli FtsH protease spans

0167-4889/$ – see front matter © 2012 Elsevier B.V. All rights reserved. doi:10.1016/j.bbamcr.2012.03.016 382 H. Janska et al. / Biochimica et Biophysica Acta 1833 (2013) 381–387 the plasma membrane twice and exposes both the ATPase and the mitochondria two AAA complexes are present: the homo-oligomeric proteolytic domain into the cytoplasm [11]. In contrast, two types of i-AAA complex composed of Yme1 subunits and the hetero-oligomeric AAA protease complexes with a different topology, i-AAA and m-AAA, m-AAA complex built of homologous Yta10 (Afg3) and Yta12 (Rca1) are found in the inner membrane of yeast [12],human[13–15] and subunits [12,27]. Mammalian mitochondria also contain a homo- plant [4,5] mitochondria. The i-AAA proteases span the inner mem- oligomeric i-AAA complex [28] but, unlike yeast, they have multiple brane once and expose their catalytic domains to the mitochondrial m-AAA complexes. Two such complexes from human mitochondria are intermembrane space, while the m-AAA proteases with two trans- known: a hetero-oligomeric one composed of paraplegin and AFG3L2 membrane regions have their active sites directed toward the matrix. In subunits, and homo-oligomeric assembled from AFG3L2 subunits alone chloroplasts, four FtsHs with one transmembrane domain (AtFtsH1, [29,30]. In mice three types of m-AAA complexes have been found: AtFtsH2, AtFtsH5 and AtFtsH8) have been detected in the same one hetero-oligomeric AFG3L1/paraplegin and two homo-oligomeric thylakoid membrane complex with the catalytic domains facing the composed of AFG3L1 or AFG3L2 [30]. Surprisingly, in both human and stroma [16]. Chloroplast AtFtsH7, 9 and 12 having two membrane- mouse paraplegin is incapable of self-assembling. Similarly to the spanning domains as well as AtFtsH11 with a single transmembrane mammals, two A. thaliana m-AAA proteases, AtFtsH3 and AtFtsH10, are region have recently been found in chloroplast envelope [17], but their able to form hetero-oligomeric as well as homo-oligomeric complexes topology in this membrane is unknown. The subplastidial localization of [5]. Based on the transcript and protein abundance, the homo- AtFtsH6 has not been reported yet. oligomeric complex of AtFtsH3 is predominant in A. thaliana leaves. While in yeast and mammals only one homo-oligomeric i-AAA 3. Architecture of high-molecular AAA/FtsH complexes complex exists, in A. thaliana two mitochondrial i-AAA proteases, AtFtsH4 and AtFtsH11, form two independent homo-oligomeric In mitochondria as well as in chloroplasts the AAA/FtsH proteases complexes [4]. The identification of two AtFtsH4-like proteases in form large complexes in the membrane, built up of identical or closely rice suggests, however, that the oligomeric composition of mitochon- related subunits. drial i-AAA complexes is probably species-specific in plants. So far, the presence of a hetero-oligomeric complex comprising four isomers 3.1. Hexameric ring structure and mode of action of AAA/FtsH proteases of two types FtsH5/FtsH1 (Type A) and FtsH2/FtsH8 (Type B), has been documented in A. thaliana chloroplasts [31,32]. The presence of The crystal structures of eubacterial FtsH cytosolic domains both types of subunits is essential, but the duplicated genes within a [10,18,19] and the AAA domain of human paraplegin [20] together type are functionally redundant. The major isoforms are FtsH2 (also with the recently reported electron cryomicroscopy (cryo-EM) designated VAR2) and FtsH5 (VAR1) while FtsH1 and FtsH8 appear to structure of full length yeast m-AAA protease [21] imply that the function as minor components [6,32]. However, their exact stoichi- AAA/FtsH complexes consist of two hexameric rings, one formed by ometry remains unclear [33]. Additionally, based on colocalization the AAA modules and the other by the protease moieties. The ATPase and coexpression studies, at least two other complexes composed of domains form the entrance to an internal cavity harboring the FtsHs are postulated to be present in the A. thaliana chloroplast proteolytic sites. Additionally, the cryo-EM study suggests that the envelope membrane [34]. One of them is formed by a homologous transmembrane and intermembrane regions of yeast m-AAA are pair FtsH7 and FtsH9 whereas the second by FtsH12 and the inactive separated from the ring structure, creating a gap large enough to FtsHs (FtsHi) lacking all three amino acids necessary for zinc binding. accommodate unfolded but not folded polypeptides. Up to now, no The oligomeric state of the remaining chloroplast FtsH proteases in crystal structure of plant AAA protease has been established, but it is A. thaliana, FtsH11 and FtsH6, is unknown. expected that they also oligomerize into hexameric ring structures. Studies on the oligomeric nature of the complexes formed by FtsHs In spite of this structural insight, the actual mode of action of the uncover an interesting functional aspect. With the exception of yeast, AAA proteases is still not fully understood. A model based on studies in where the m-AAA complex is inactive in the absence of one subunit, it bacteria and yeast attempts to explain how proteins are degraded by has been demonstrated that in human, murine and plant mitochon- the FtsH complexes. An understanding of the mechanisms of other dria the hetero-oligomers can be functionally substituted by homo- modes of action of the AAA proteases such as protein processing or oligomers. Paraplegin deficiency in human does not result in a loss of dislocation across the membrane is just emerging. It is almost certain the housekeeping activity of the m-AAA proteases; instead this that the AAA proteases cannot recognize specific sequences in proteins activity is substituted by homo-oligomeric AFG3L2 complexes [30].A even during a processing reaction and that they only sense unstruc- functional redundancy between the homo- and hetero-oligomeric tured and flexible parts of substrates and then degrade them until a murine m-AAA complexes was observed in complementation studies tightly folded domain prevents further degradation [22].Sucha in yeast [35]. Similarly, in A. thaliana mitochondria the housekeeping mechanism is in agreement with the FtsH proteases having a low un- functions of the homo- and hetero-oligomeric complexes containing folding activity [23]. Thus far, the best known mechanism of substrate AtFtsH3 can be substituted by AtFtsH10 homo-oligomers [5]. Inter- recognition relies on free, unstructured N- or C-terminal ends ap- estingly, in the human only one of the two m-AAA subunits can homo- proximately 10–20 aa long [24]. A study of substrate recognition has oligomerize [30]. Moreover, exchange of only two amino acid residues revealed distinct substrate binding sites at the outer surface of the yeast in the proteolytic domain confers homo- or hetero-oligomeric mode i-AAA complex suggesting the existence of alternative pathways for of assembly on the m-AAA protease subunits in yeast [21]. There is no entry of different substrates into the central pore of the AAA ring [25]. data so far, that in chloroplasts the homo-complex can replace the Moreover substrate-specific cofactors have been shown to modulate hetero-complex, but it has been documented that within a given type the initial substrate–enzyme interaction. Once the substrate is bound the chloroplast isomers are functionally interchangeable, whereas to the central pore, it is believed that in analogy to other proteolytic between the different types they are not [31,32,36]. In other words, at AAA+complexes, it is translocated in an ATP hydrolysis-driven manner least one isomer from each type appears to be necessary for a stable into the proteolytic chamber where it is degraded into oligopeptides assembly of a functional chloroplast FtsH complex. smaller than 3 kDa, mostly between 10 and 20 amino acids [26]. Interestingly, it seems that a variable composition of the oligo- meric AAA complexes could lead to their altered substrate specificity. 3.2. Homo- and hetero-oligomeric complexes of AAA/FtsH proteases It was reported that the processing of OPA1, a dynamin-like GTPase of the mitochondrial inner membrane, was restored in yeast cells lacking Table 1 presents sizes and compositions of experimentally verified m-AAA subunits upon expression of the mammalian m-AAA but the AAA/FtsH complexes from yeast, humans, mice and A. thaliana. In yeast processing efficiency depended on the subunit composition of the H. Janska et al. / Biochimica et Biophysica Acta 1833 (2013) 381–387 383

Table 1 Experimentally identified AAA proteases complexes in Eukaryota.

Organism Localization Name of Nature of complex Molecular mass of complex (method) Interacting subunit (reference) proteins

Saccharomyces Mitochondria i-AAA Yme1p Homo-oligomer [12] ~850 kDa Mgr1p and Mgr3p cerevisiae (Yta11p) (gel filtration) m-AAA Yta10p Hetero-oligomer [40] ~900 kDa 2000 kDaa Prohibitins (Afg3p) (gel filtration) Yta12p (Rca1p) Mouse Mitochondria m-AAA Paraplegin Hetero-oligomer [30] ~900 kDa Prohibitins AFG3L2 Homo- and (immunoprecipitation/immunoblotting) AFG3L1 hetero-oligomer [30] Homo sapiens Mitochondria i-AAA YME1L Homo-oligomer [28] ~900 kDa Prohibitins m-AAA Paraplegin Hetero-oligomer [29] (gel filtration) AFG3L2 Homo- and hetero-oligomer [29] Arabidopsis Mitochondria i-AAA AtFtsH4 Homo-oligomer [4] ~1500 kDa – thaliana (BN-PAGE) AtFtsH11 Homo-oligomer [4] ~1500 kDa – (BN-PAGE) m-AAA AtFtsH3 Homo- and ~1000 kDa Prohibitins AtFtsH10 hetero-oligomer [5] 2000 kDaa (BN-PAGE, immunoprecipitation) Chloroplasts AtFtsH1 Hetero-oligomer [6,31] ~400–450 kDa – AtFtsH2 (sucrose density gradient; AtFtsH5 gel filtration; 2-D green gel) AtFtsH8

a Represents a supercomplex of m-AAA proteases and prohibitins. mammalian complex. The homo-oligomeric complexes of human or In the case of the mitochondrial i-AAA complex, interacting proteins, murine m-AAA cleaved OPA1 with a higher efficiency than the hetero- Mgr1 and Mgr3, have so far only been identified in yeast [41].Homologs oligomeric ones [37]. The tissue-specific differences in the abundance of these proteins are found exclusively in fungi suggesting that this of mitochondrial FtsH isoforms reported for mammals [30] and plants interaction is not conserved in mammals or plants. The complex [5] also support the view about the tissue-specific substrate specificity composed of Mgr1 and Mgr3 seems to act as an adaptor to help target of the AAA proteases. Developmental and tissue-specific patterns substrates to the i-AAA complex. Interestingly, this complex remains of accumulation of FtsH proteases have also been documented in stable even in the absence of i-AAA. A. thaliana chloroplasts [38]. 4. Molecular functions of AAA/FtsH proteases in mitochondria 3.3. Interacting proteins and chloroplasts

The fact that the molecular sizes of the AAA/FtsH complexes 4.1. Degradation of non-native (unassembled, damaged) organellar proteins evaluated by BN-PAGE electrophoresis and/or size exclusion chroma- tography are much larger (Table 1) than the predicted molecular sizes The main function of organellar AAA/FtsH proteases is selective of hexamers of 70–80 kDa subunits implies that several hexamers are degradation of non-assembled, incompletely assembled and/or dam- associated together and/or that other components in addition to the aged membrane-anchored proteins. Thus, these enzymes play a central AAA/FtsH proteases are part of these high molecular weight structures role in the quality control of membrane proteins in mitochondria and in vivo. This second possibility has experimental support in the case of chloroplast. Peptides produced by the action of the AAA/FtsH proteases FtsH from bacteria [39], mitochondrial m-AAA from yeast [40] and are either exported from the organelle [45] or degraded in situ to amino plants [5], as well as yeast i-AAA complex [41]. acids by various oligopeptidases [46]. The mitochondrial m-AAA complexes in yeast [40] and plants [5], A limited number of substrates of the protein quality control have similarly to the bacterial FtsH complex [39], are part of large super- been identified for yeast and human i-andm-AAA proteases. Non- complexes that contain, in addition to FtsHs, a second complex assembled subunit II of cytochrome oxidase [47–49],subunitsof composed of prohibitins or, in the case of bacteria, related proteins prohibitin complex [45], Yme2 protein [50] as well as external NADH termed HfIKC. In yeast two (PHB1, PHB2) while in A. thaliana five dehydrogenase [51] has been reported to be substrates of the yeast (AtPHB1, AtPHB2, AtPHB3, AtPHB4 and AtPHB6) highly homologous i-AAA protease. Recently, non-assembled forms of several mitochon- proteins assemble into a prohibitin complex [40,42].Inaddition,in drial proteins including Ndufb6, a subunit of complex I and two subunits the A. thaliana prohibitin complex two other mitochondrial proteins of complex IV (Cox4, Cox2) were uncovered as proteolytic substrates of have been identified: isocitrate dehydrogenase IDH1, and a protein of the human i-AAA protease [28]. On the other hand, non-assembled unknown function [42]. It should be emphasized that in contrast to mitochondrially encoded subunits of the respiratory complexes: Cob, yeast, where a loss of the prohibitin complex has no effect on m-AAA Cox1, Cox3 as well as the F1F0 ATP synthase subunits 6, 8 and 9 were assembly, in A. thaliana stable prohibitin—independent high molecular found to be degraded by the yeast m-AAA protease [27,52].Inaddition weight complexes of the m-AAA proteases could not be identified [5]. to these integral membrane proteins, the yeast m-AAA protease Thus, the stability of the m-AAA complexes in plant cells seems to degrades peripheral membrane proteins such as Atp7 [53]. Further- depend on the presence of prohibitins. The exact role of the conserved more, both unassembled full-length and truncated Cox1 proteins were interaction between FtsHs and prohibitins is still not fully understood, recognized as substrates of the human m-AAA protease AFG3L2 [54]. but based on a study in yeast, prohibitins have been postulated to act as No substrates of the protein quality control of the plant mito- negative regulators of the m-AAA proteolytic activity [43] and/or a chondrial AAA proteases have been identified so far. However, it has scaffold limiting the mobility of the m-AAA proteases [44]. been suggested that the oxidatively damaged mitochondrial proteins 384 H. Janska et al. / Biochimica et Biophysica Acta 1833 (2013) 381–387 which accumulate in aging plants under stressful conditions are quality control, such as processing of pre-proteins, dislocation of natural substrates of AtFtsH4, one of the i-AAA proteases in A. thaliana membrane proteins or degradation of regulatory proteins. mitochondria [55,56]. This was concluded from the observation that The first evidence that mitochondrial AAA proteases could perform the amount of mitochondrially oxidized proteins increases signifi- limited proteolysis and act as processing peptidases came from studies cantly with age in A. thaliana lacking the AtFtsH4 protease. This view in yeast where the m-AAA protease mediates maturation of MrpL32, a was also supported by a transmission electron microscopy (TEM) component of the large subunit of mitochondrial ribosome [35].Later,it analysis showing tiny accumulations of electron-dense material, was found that AFG3L1 and AFG3L2, subunits of the m-AAA complex in presumably aggregates of oxidized proteins, in the mitochondrial mice, mediate their own maturation in an autocatalytic manner after matrix of old, but not young, ftsh4 plants [55]. It seems that in aging their cleavage by the mitochondrial processing peptidase (MPP) [68]. A. thaliana the amount of oxidatively damaged mitochondrial proteins They are also required for maturation of the third subunit of mouse reaches a certain threshold above which insoluble aggregates are m-AAA complex, paraplegin. Furthermore, in mammalian cells the formed. The accumulation of oxidatively damaged mitochondrial i-andm-AAA proteases have been linked to the processing of the membrane proteins was also observed in human YME1-deficient cells dynamin-related GTPase OPA1 (optic atrophy type 1) which is mainly after treatment with hydrogen peroxide [28]. Thus, loss of human or involved in mitochondrial inner membrane fusion and remodeling [69]. A. thaliana i-AAA led to increased susceptibility to mitochondrial It came as a great surprise that mitochondrial AAA proteases, membrane protein oxidation. besides cleaving proteins, can also mediate protein dislocation across An involvement of the chloroplast FtsH proteases in the degrada- the inner mitochondrial membrane [70,71]. It was found that the tion of unassembled or oxidatively damaged thylakoid proteins has yeast m-AAA protease mediates ATP-dependent membrane disloca- also been reported. Improperly assembled Rieske FeS protein was tion of a ROS-scavenger protein, cytochrome c peroxidase, allowing rapidly degraded by FtsH protease in isolated chloroplasts and this its intramembrane cleavage by rhomboid protease [71]. The evidence degradation was stimulated by light [57]. The degradation of photo- for the translocation function of i-AAA protease also comes from damaged proteins by chloroplast FtsH is not limited to unassembled yeast. It has been shown that Yme1 mediates import of mammalian proteins, but functionally assembled proteins that have undergone polynucleotide phosphorylase (PNPase) heterologously expressed in photooxidative damage can also be substrate for these proteases. The yeast [70]. It should be emphasized that the translocation function of best-known example is D1 protein of photosystem II (PSII) [58–61]. AAA proteases does not depend on their proteolytic activity. FtsH plays a crucial role in degradation of the D1 protein damaged not Another function of i-AAA proteases not directly connected with only by light but also by reactive oxygen species formed during protein quality control is their involvement in the turnover of moderate heat stress [62]. In vitro studies indicated that under dark- regulatory mitochondrial proteins under normal conditions. Recently, induced senescence or high-light treatment the PSII light-harvesting it has been shown that yeast i-AAA controls the stability of two proteins Lhcb1 and Lhcb2 could be substrates of AtFtsH6 [63]. intermembrane proteins, Ups1 and Ups2, which regulate the bio- However, that finding was not confirmed in vivo [64]. genesis of the mitochondria-specific phospholipids, cardiolipin and phosphatidylethanolamine [72]. 4.2. Assembly/stability of membrane complexes 5. Link between molecular functions and phenotypic alterations Yeast, mammalian and plant cells lacking mitochondrial AAA Based on the available reports, inactivation of either yeast AAA proteases exhibit a deficiency in the assembly of oxidative phosphor- protease results in pleiotropic defects [73].Intheabsenceofboth ylation complexes [29,65,66]. It was demonstrated that the formation m-andi-AAA, yeast cells are inviable. The phenotypic consequences of of the cytochrome c oxidase and the bc1 complex in yeast is under adeficiency of the AAA proteases in multicellular organisms are tissue- control of proteolytic activity of the m-AAA protease [65]. More specific and in some cases are not readily visible due to functional specifically, inactivation of m-AAA impairs mitochondrial translation redundancy. and thus limits the availability of mitochondrially encoded proteins [35,65]. On the other hand, although not yet explicitly demonstrated, 5.1. Physiological consequences of inactivation of m-AAA in yeast, it was postulated that the chaperone-like activity uncoupled from the mammals and plants proteolytic function of i- and m-AAA proteases is involved in the assembly of complex V in S. cerevisiae [67]. Genetic evidences indicate It has been suggested that all the phenotypes observed in m-AAA interaction of Hsp90 with i- and m-AAA complexes during complex V protease-deficient yeast cells, including the loss of respiratory com- assembly, particularly under stressful conditions. petence, are largely explained by an impaired maturation of the Similarly, barring AtFtsH11, the remaining A. thaliana mitochon- mitochondrial ribosomal protein MrpL32 rather than a deleterious drial AAA proteases (AtFtsH3, 4 and 10) are needed for the assembly/ effect of accumulation of non-native membrane proteins [74]. The stability of complex I and complex V [66]. The assembly/stability processing of MrpL32 is required for mitochondrial ribosome as- of complex I requires mainly a functional m-AAA complex, while sembly and thus for the synthesis of all mitochondrially encoded complex V assembly/stability is under control of both the m-AAA and proteins, including subunits of the oxidative phosphorylation system. i-AAA proteases. Furthermore, the activity/amount ratio for complex V Complementation studies in yeast have revealed that murine m-AAA in plants lacking AtFtsH4 indicates that this protease is not only proteases are able to process yeast as well as murine MrpL32 [35]. involved in complex V assembly/stability but also protects it against Furthermore, A. thaliana m-AAA complexes are also functional toward an unidentified catalytic defect [66]. In view of the fact that AtFtsH4 is yeast MrpL32, however, up to now there is no direct evidence that able to degrade oxidatively damaged mitochondrial proteins [55],it they are able to process a plant homolog of MrpL32 [5]. Taken to- is likely that the catalytic defect of complex V in ftsh4 mutants is gether, these results highlight conservation of the processing activity associated with selective oxidation of this complex. of yeast, mammalian and plant m-AAAs. Mutations in subunits of the human m-AAA complex, paraplegin 4.3. Other molecular functions of AAA/FtsH proteases not directly and AFG3L2, lead to different neurodegenerative disorders. A loss of connected with protein quality control paraplegin function leads to a recessive form of hereditary spastic paraplegia (HSP) characterized by progressive degeneration of axons A growing number of reports indicate additional functions of the in the corticospinal tract and posterior columns [13]. On the other AAA/FtsH proteases that are not directly connected with protein hand, mutations in human Afg3l2 gene have been linked to a form of H. Janska et al. / Biochimica et Biophysica Acta 1833 (2013) 381–387 385 spinocerebellar ataxia (SCA28), a neurological disorder caused by membrane, altered cristae morphology, impaired cell proliferation and degeneration of the cerebellum [75,76]. apoptotic resistance [28]. Further studies will be required to understand Neurodegeneration symptoms were also observed in a transgenic the underling molecular mechanism of these phenotypes. mouse lacking m-AAA subunits, which was used as a model of human diseases. Like in HSP, late-onset degeneration of spinal and peripheral 5.3. Physiological consequences of inactivation of chloroplastic FtsHs axons was observed in mouse mutants lacking paraplegin [77]. The loss of the AFG3L2 protein in mice caused a very severe phenotype The A. thaliana FtsH complex localized to the thylakoid membrane is characterized by early-onset developmental defects in the brain, unique in that it is composed of four isoforms. A loss of either of the two spinal cord and muscle [78]. In consequence, homozygous Afg3l2 mice more abundant ones, AtFtsH2 (var2 mutant) or AtFtsH5 (var1 mutant) did not survive over 16 days. However, heterozygous Afg3l2 mice do results in severe or weak leaf-variegated phenotypes, respectively, not show a remarkable phenotype up to 3 months of age. None of the while a lack of remaining two expressed at much lower levels, AtFtsH8 phenotypes of Afg3l2−/− mice is understood at the molecular level or AtFtsH1, does not cause obvious phenotypes [6,60,85,86].Interest- but it appears unlikely that abnormal processing of MrpL32 underlies ingly, the var2 and var1 mutants have green cotyledons, but their neurodegeneration [79]. This opinion is based on the observation that subsequent true leaves are variegated with a gradually decreasing ratio no defects of mitochondrial protein synthesis have been observed in of white to green sectors [38]. Whereas cells in the green leaf sectors the Afg3l2 null mutants exhibiting the severe neurological phenotype. contain normal-appearing chloroplasts, those in the white sectors The processing of MrpL32 in these mutants could be performed by contain undifferentiated plastids [85,87]. It seems that the variegated the residual AFG3L1-containig m-AAA protease or by another as yet phenotype of the var mutants results from improper thylakoid for- unknown protease. mation and is separable from a defect in the photodamaged D1 protein Phenotypic observations have been so far reported only for turnover [38,61,88].However,recentfindings using a suppressor-of- A. thaliana mutants lacking one subunit of the m-AAA complex. The variegation mutant, svr4, suggest a link between variegation and single mutants displayed no severe phenotypic deviations under typical photooxidative damage of PSII [89].Identification of var2 suppressor laboratory growth conditions, however, they were slightly different lines showed that multiple mechanisms are able to compensate for the from wild-type plants in terms of size and seed productivity in the field lack of AtFtsH2 during early chloroplast biogenesis [90].Thefirst [34]. The molecular basis of these phenotypes is not understood, but the reported suppression of variegation was caused by down-regulated m-AAA complex seems the most important during early stages of plant expression of gene encoding ClpC2, a plastid-localized Hsp100 [91]. development since no phenotypic alterations were been reported Unexpectedly, the majority of var2 suppressor genes encode compo- visible when older plants were placed outdoors. nents related to protein biosynthesis in plastids [88,92–94].Taken together, further research is necessary to understand the precise 5.2. Physiological consequences of inactivation of i-AAA in yeast, mechanisms responsible for suppression of variegation. mammals and plants Interestingly, it was demonstrated that leaf variegation of plants lacking both of Type B isomers (FtsH2, FtsH8) could be rescued by In contrast to yeast m-AAA, the molecular basis of several distinct expressing a proteolytic inactive FtsH2, suggesting dispensability yeast phenotypes associated with a loss of the i-AAA complex, like protease activity of these isomers for proper chloroplast development respiratory deficiency at high temperature, slow growth on rich glucose [95]. Thus, one may speculate that the appearance of the variegated medium at low temperature or in the absence of mitochondrial DNA, phenotype is independent of proteolysis and only the chaperone func- increased escape of DNA from mitochondria [80,81],alteredmitochon- tion of the complex is responsible for the correct thylakoid formation drial morphology [82], decreased chronological life span and decreased [34]. Although the mechanism of variegation is still not solved, several long term spore viability [83] are only partially understood. It is thought lines of evidence indicate that a threshold level of FtsHs is necessary for that impaired proteolysis of as yet undiscovered substrate proteins a proper thylakoid formation [36,38,87]. The threshold depends on the rather than deleterious effects of misfolded polypeptides is responsible developmental stage and environmental conditions and the fate of cells for these distinct phenotypes [74]. However, it has been postulated is determined at an early stage of plastid development. recently that a primary function of i-AAA in yeast is associated with the In turn, no variegation in leaf color was observed in any of the assembly and disassembly of the ATP synthase, particularly under stress A. thaliana ftsh11 mutants. Instead, the growth and development of conditions [67]. mutant plants at all stages examined was arrested after exposure to a Similarly, a problem with the assembly/stability of ATP synthase was moderately elevated temperature, but not to high light [96]. The also detected in A. thaliana plants lacking AtFtsH4 throughout the entire mechanism by which AtFtsH11 contributes to A. thaliana thermo- life cycle [55,56], which therefore could not be responsible alone for the tolerance is not clear but it was demonstrated that it was indepen- phenotypic alterations observed only in aging ftsh4 mutants. Asym- dent of the induction of heat-shock genes. The remaining chloroplast metric shape and irregular serration of leaf blades of aging mutants proteases are less well studied, however, it is known that AtFtsH12 were correlated with symptoms of oxidative stress, including accumu- knockout results in embryo-lethality, while ftsh6 mutants do not have lation of oxidatively damaged proteins. A link between the lack of the a visible phenotype [6,34]. AtFtsH4 protease, accumulation of oxidized proteins, dysfunctional mitochondria and altered leaf morphology was hypothesized. It was 6. Outside events affecting mitochondrial/chloroplast quality suggested that AtFtsH4, in addition to its housekeeping function control systems associated with the assembly/stability of ATP synthase, plays a more specific role at the end of vegetative growth associated with de- There is some experimental evidence suggesting that protein gradation of oxidatively damaged proteins. quality control in mitochondria and chloroplasts may be affected by In contrast to yeast and A. thaliana, information about the events outside the respective organelles. Some examples of such physiological role and importance of mammalian mitochondrial i-AAA events are described below. protease is rather scarce. Remarkably, the human i-AAA protease In yeast a mutation in a gene for a regulatory subunit of the 26S YME1L was found to be involved in constitutive OPA1 cleavage but at a protease has been reported to suppress some of the growth defects site other than that recognized by m-AAA [84]. The physiological role of caused by a disruption of Yme1 [82]. This result indicates a possible this cleavage is still unclear. It was reported recently, that knockdown of association between the cytosolic 26S protease and the mitochondrial YME1L in mammalian cells (HEK293) led to excessive accumulation protein quality control system. Another studies in yeast showed that of non-assembled and oxidatively damaged proteins in the inner aging-related mitochondrial degeneration caused by deletion of 386 H. Janska et al. / Biochimica et Biophysica Acta 1833 (2013) 381–387

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