Molecular Machinery of Mitochondrial Fusion and Fission

Mitochondria generate energy by oxidative phosphorylation; play a crucial role in iron-sulfur cluster assembly; and participate in intermediary metabolism, calcium signaling, and apoptosis. They are bounded by a double membrane and contain ∼800 (yeast) to 1500 (human) different proteins. Although the vast majority of mitochondrial proteins are encoded in the nucleus and post-translationally imported into the organelle, a handful of proteins required for respiration are encoded by the mitochondrial genome. In many eukaryotic cell types, mitochondria continuously move along cytoskeletal tracks and frequently fuse and divide (1Bereiter-Hahn J. Int. Rev. Cytol. 1990; 122: 1-63Crossref PubMed Scopus (279) Google Scholar). In recent years, it became clear that this dynamic behavior is important for many mitochondrial functions in cell life and death (2Chan D.C. Cell. 2006; 125: 1241-1252Abstract Full Text Full Text PDF PubMed Scopus (1518) Google Scholar). Here, I will briefly summarize the cellular roles of mitochondrial dynamics and discuss the molecular machinery mediating mitochondrial membrane fusion and fission. Mitochondrial morphology and copy number depend on the balance of fusion and fission activities. A shift toward fusion enables the cell to build extended interconnected mitochondrial networks, whereas a shift toward fission generates numerous morphologically and functionally distinct small spherical organelles. This adaptation of the mitochondrial compartment to cellular demands is critical for a number of important processes (Fig. 1). Large mitochondrial networks are frequently found in metabolically active cells. They consist of extended and interconnected mitochondrial filaments and act as electrically united systems. These networks enable the transmission of mitochondrial membrane potential from oxygen-rich to oxygen-poor areas and thereby allow an efficient dissipation of energy in the cell (3Skulachev V.P. Trends Biochem. Sci. 2001; 26: 23-29Abstract Full Text Full Text PDF PubMed Scopus (368) Google Scholar). Furthermore, the connectivity of the mitochondrial network is an important factor that determines the cell's response to calcium signals (4Szabadkai G. Simoni A.M. Bianchi K. De Stefani D. Leo S. Wieckowski M.R. Rizzuto R. Biochim. Biophys. Acta. 2006; 1763: 442-449Crossref PubMed Scopus (161) Google Scholar), and fusion of mitochondria is an essential step in certain developmental processes such as embryonic development (5Chen H. Detmer S.A. Ewald A.J. Griffin E.E. Fraser S.E. Chan D.C. J. Cell Biol. 2003; 160: 189-200Crossref PubMed Scopus (1783) Google Scholar) and spermatogenesis (6Hales K.G. Fuller M.T. Cell. 1997; 90: 121-129Abstract Full Text Full Text PDF PubMed Scopus (478) Google Scholar). In addition to its role in network formation, fusion serves to mix and unify the mitochondrial compartment, an activity that is thought to constitute a defense mechanism against aging. It is estimated that 1–5% of the oxygen consumed during oxidative phosphorylation is converted to ROS 2The abbreviations used are: ROS, reactive oxygen species; CMT, Charcot-Marie-Tooth disease. as an unavoidable by-product of respiratory chain function. As mtDNA is directly located at the site of ROS production, it is particularly vulnerable to ROS-mediated mutations. These mutations accumulate with age until a bioenergetic threshold is breached, resulting in mitochondrial dysfunction(definition). The mitochondrial theory of aging predicts that an accumulation of mtDNA mutations eventually leads to age-associated pathologies and death (7Balaban R.S. Nemoto S. Finkel T. Cell. 2005; 120: 483-495Abstract Full Text Full Text PDF PubMed Scopus (3285) Google Scholar). Fusion of mitochondria counteracts the manifestation of respiratory deficiencies because it allows complementation of mtDNA gene products in heteroplasmic cells that have accumulated different somatic mutations (8Sato A. Nakada K. Hayashi J. Biochim. Biophys. Acta. 2006; 1763: 473-481Crossref PubMed Scopus (42) Google Scholar). Similar to fusion, mitochondrial fission also plays a key role in cell life and death. As mitochondria are propagated by growth and division of pre-existing organelles, mitochondrial inheritance depends on mitochondrial fission during cytokinesis (9Warren G. Wickner W. Cell. 1996; 84: 395-400Abstract Full Text Full Text PDF PubMed Scopus (228) Google Scholar). Furthermore, mitochondrial division is important for several developmental and cell differentiation processes, including embryonic development in Caenorhabditis elegans (10Labrousse A.M. Zappaterra M.D. Rube D.A. van der Bliek A.M. Mol. Cell. 1999; 4: 815-826Abstract Full Text Full Text PDF PubMed Scopus (513) Google Scholar) and formation of synapses and dendritic spines in neurons (11Li Z. Okamoto K. Hayashi Y. Sheng M. Cell. 2004; 119: 873-887Abstract Full Text Full Text PDF PubMed Scopus (1126) Google Scholar). Last but not least, the mitochondrial fission machinery actively participates in the programmed cell death pathway (apoptosis) by inducing fragmentation of the mitochondrial network prior to cytochrome c release and caspase activation (12Youle R.J. Karbowski M. Nat. Rev. Mol. Cell Biol. 2005; 6: 657-663Crossref PubMed Scopus (622) Google Scholar). The major components of the mitochondrial fusion and fission machineries have been evolutionarily conserved from yeast to man (Table 1). Due to this conservation and the availability of sophisticated genetic, cytological, and biochemical assays, bakers' yeast (Saccharomyces cerevisiae) emerged as one of the prime model organisms to study the molecular mechanisms of mitochondrial membrane fusion and fission (13Okamoto K. Shaw J.M. Annu. Rev. Genet. 2005; 39: 503-536Crossref PubMed Scopus (594) Google Scholar, 14Merz S. Hammermeister M. Altmann K. Dürr M. Westermann B. Biol. 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