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Mitochondrial Dynamics and Inheritance During Cell Division, Development and Disease

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Mitochondrial Dynamics and Inheritance During Cell Division, Development and Disease REVIEWS Mitochondrial dynamics and inheritance during cell division, development and disease Prashant Mishra1 and David C. Chan1,2 Abstract | During cell division, it is critical to properly partition functional sets of organelles to each daughter cell. The partitioning of mitochondria shares some common features with that of other organelles, particularly in the use of interactions with cytoskeletal elements to facilitate delivery to the daughter cells. However, mitochondria have unique features — including their own genome and a maternal mode of germline transmission — that place additional demands on this process. Consequently, mechanisms have evolved to regulate mitochondrial segregation during cell division, oogenesis, fertilization and tissue development, as well as to ensure the integrity of these organelles and their DNA, including fusion–fission dynamics, organelle transport, mitophagy and genetic selection of functional genomes. Defects in these processes can lead to cell and tissue pathologies. Oxidative phosphorylation Organelles are a distinguishing feature of eukaryotic cells. controls mitochondrial structure and, depending on the (OXPHOS). A biochemical During somatic cell proliferation, they must segregate cell type, the numerous separate mitochondria in the cell pathway within mitochondria properly to daughter cells and, during germline inherit­ can shift to form a single interconnected membranous that generates ATP through the ance, a highly functional population of organelles must structure. oxidation of nutrients. be transmitted to the offspring. One such organelle is the Mitochondria have two features that constrain their 1 Endosymbiotic theory mitochondrion , which is best known for its critical func­ segregation. First, they have a genome (mitochondrial A theory postulating that tion in energy production via oxidative phosphorylatio­n DNA (mtDNA)), which encodes crucial bioenergetic genome-containing organelles, (OXPHOS) — a pathway that generates many more functions (BOX 1). Each mitochondrion contains one such as mitochondria and chloroplasts, are derived from ATP molecules per glucose molecule than the glyco­ or more mtDNA molecules, which are organized into bacteria that underwent lysis pathway. Mitochondria also have important roles mtDNA–protein complexes known as nucleoids. In pro­ endosymbiosis with ancestral in other types of metabolism, in regulating intracellular­ liferating cells, the partitioning of mitochondria to daugh­ eukaryotic cells. calcium concentration and signalling in neurons, in the ter cells must also result in proper distribution of mtDNA. assembly of iron–sulphur clusters that are important Second, mitochondria in mammals are transmitted to for oxidatio­n–reduction reactions2, in apoptosis­ 3 and in subsequent generations exclusively through the maternal innate immunity4. lineage. Because of this uniparental inheritance pattern, According to the endosymbiotic theory, mitochon­ mtDNA lacks the benefits of recombination arising from 1Division of Biology and dria are descendants of ancient bacteria that entered sexual reproduction. However, mechanisms have evolved 5 Biological Engineering, into a symbiotic relationship with primitive host cells . to reduce the chance of transmitting pathogenic mtDNA California Institute of Mitochondria retain several characteristics of their puta­ mutations to offspring. In some cases, these mechanisms Technology, Pasadena, tive bacterial ancestors: a double membrane, a proteome fail, and maternally inherited disorders termed mitochon­ California 91125, USA. 2Howard Hughes Medical similar to that of α‑proteobacteria and the ability to syn­ drial encephalomyopathies arise when a significant load Institute, California Institute thesize ATP via a proton gradient created across their of mtDNA mutations are passed to the offspring. These of Technology, Pasadena, inner membrane (BOX 1). In addition to having these bac­ diseases are characterized by reduced mitochondrial func­ California 91125, USA. terial characteristics, mitochondria undergo membrane tion, with clinical signs being most pronounced in tissues Correspondence to D.C.C. remodelling through cycles of fusion (in which two with high energy consumption. e‑mail: [email protected] doi:10.1038/nrm3877 mitochondria join to form a single mitochondrion) and Given that mitochondria function in diverse cellu­ Published online fissio­n (in which a single mitochondrion divides into two lar processes and that their dysfunction is implicated in 17 September 2014 mitochondria)6 (BOX 2). The balance of fusion and fission several diseases, it is important to have an understanding 634 | OCTOBER 2014 | VOLUME 15 www.nature.com/reviews/molcellbio © 2014 Macmillan Publishers Limited. All rights reserved REVIEWS Genetic bottlenecks of mitochondrial dynamics, segregation and germline Mitochondrial dynamics and segregation Drastic reductions in the inheritance. In this Review, we first outline the molecu­ In discussing mitochondrial inheritance, ‘proper parti­ genetic diversity of a lar mechanisms that ensure proper partitioning of mito­ tioning’ of the mitochondria implies that mitochondria population. chondria during cell division: the fusion–fission cycle, and mtDNA are distributed equally to daughter cells (in mitochondrial interactions with cytoskeletal elements the case of symmetric cell division), and that the inher­ and the endoplasmic reticulum (ER), and mitophagy. ited mitochondria are highly functional. In mammalian We then discuss the specific regulation of mtDNA cells that divide symmetrically, segregation could, in inheritance and its uniparental transmission through principle, be a largely passive process, as long as there are the maternal lineage, including the evidence for genetic mechanisms to ensure a homogeneous and evenly dis­ bottle­necks during oogenesis and embryonic develop­ persed spatial distribution of organelles throughout the ment, and the mechanisms preventing transmission of cell soma (FIG. 1). As discussed below, faithful segregation paternal mitochondria to offspring. Throughout, our is facilitated by the induction of mitochondrial fission main focus is on mammalian mitochondria, but studies during the G2 and mitosis phases of the cell cycle (FIG. 1b) carried out in yeast, worms and flies are discussed in and by the interaction of mitochondria with cytoskeletal cases in which they have provided substantial insights. and ER elements, which are spread throughout the cell Box 1 | The mitochondrial genome and oxidative phosphorylation Mitochondria contain a residual genome (mitochondrial DNA (mtDNA)), mitochondrial proteome are encoded by the nuclear genome, which is critical for their function in oxidative phosphorylation (OXPHOS). synthesized in the cytosol and imported into the mitochondria. In humans, the mtDNA is ~16.6 kilobases in length and contains 37 genes Mitochondria are double-membrane organelles consisting of an outer encoding 13 polypeptides, 2 ribosomal RNAs and 22 tRNAs (see the membrane surrounding an inner membrane of greater surface area. figure, part a). The displacement loop (D‑loop) is a regulatory sequence The space between the two membranes is termed the intermembrane that controls mtDNA replication and transcription. The 13 polypeptides space. Because of its greater surface area, the inner membrane folds back are distributed among the OXPHOS protein complexes I, III, IV and V and on itself, creating compartments termed cristae. The respiratory chain are essential for OXPHOS (cellular respiration) activity (see the figure, complexes are concentrated in the cristae membranes. Complexes I, part b). The specific mtDNA-encoded subunits are listed under each III and IV pump protons from the matrix (the compartment enclosed by respiratory chain complex. These complexes also have multiple subunits the inner membrane) to the intermembrane space, generating an encoded by the nuclear genome. Complex II is encoded entirely by the electrochemical gradient across the inner membrane that is used to nuclear genome. The 2 rRNAs and 22 tRNAs encoded by the mtDNA are power ATP production by complex V (ATP synthase). The ATP–ADP essential for the mitochondrial translational machinery that is used to translocase exports the ATP into the intermembrane space, where it generate the 13 polypeptides and, because of this, all 37 mtDNA genes freely diffuses out of the outer membrane into the cytosol. The mtDNA are critical for OXPHOS. The remaining proteins (>1,000) in the is packaged into nucleoid structures (not shown) located in the matrix. D-loop Cyt b a 12S rRNA b Outer membrane space ND6 16S rRNA Intermembrane space ND5 Inner membrane space ND1 ND4 Crista ND2 + + ND4L H H Cyt c ND3 H+ H+ COI COIII ATP6 – – COII e e ATP8 e– e– CoQ III IV II ½O2 H2O tRNA Matrix I 2H+ V FADH2 FAD rRNA NADH NADH+ ADP ATP + Regulatory sequences Pi H Complex I ND1 ND4 Cyt b COI ATP6 13 mtDNA ND2 ND4L COII ATP8 Complex III polypeptides ND3 ND5 COIII ND6 ATP Complex IV ADP Complex V ATP–ADP translocase ATP6, ATP synthase 6; CO, Cyt c oxidase subunit; CoQ, Coenzyme Q10; Cyt, cytochrome; ND, NADH–ubiquinone oxidoreductaseNature Reviewschain; Pi, inorganic | Molecular phosphate. Cell Biology NATURE REVIEWS | MOLECULAR CELL BIOLOGY VOLUME 15 | OCTOBER 2014 | 635 © 2014 Macmillan Publishers Limited. All rights reserved REVIEWS Box 2 | Mitochondrial fusion and fission in mammalian cells Continual cycles of fusion and fission result in the intermixing of the Whereas cells lacking both MFNs have no mitochondrial
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