Mechanisms of Mitochondrial Fission and Fusion

Mitochondria continually change shape through the combined actions of fission, fusion, and movement along cytoskeletal tracks. The lengths of mitochondria and the degree to which they form closed networks are determined by the balance between fission and fusion rates. These rates are influenced by metabolic and pathogenic conditions inside mitochondria and by their cellular environment. Fission and fusion are important for growth, for mitochondrial redistribution, and for maintenance of a healthy mitochondrial network. In addition, mitochondrial fission and fusion play prominent roles in disease-related processes such as apoptosis and mitophagy. Three members of the Dynamin family are key components of the fission and fusion machineries. Their functions are controlled by different sets of adaptor proteins on the surface of mitochondria and by a range of regulatory processes. Here, we review what is known about these proteins and the processes that regulate their actions.Mitochondrial movement and fission were first observed with light microscopy almost 100 years ago (Lewis and Lewis 1914). For a long time, these observations remained something of a curiosity and they were all but forgotten when electron microscopy popularized the idea that mitochondria exist as isolated sausage-shaped organelles floating in a sea of cytoplasm. Renewed appreciation for mitochondrial dynamics emerged some 20 or 30 years ago when technological advances made it much easier to track mitochondria in live cells. Careful observations, first with phase contrast microscopy, then with vital dyes and finally with targeted fluorescent proteins, showed that mitochondria continually divide and fuse, even in resting cells (Johnson et al. 1981; Bereiter-Hahn and Voth 1994; Rizzuto et al. 1996). Their lengths are determined by the balance between fission and fusion. Mitochondrial morphologies can change dramatically by shifting this balance. In some cells they fuse together, forming a single closed network, whereas in other cells or under different circumstances mitochondria convert into large numbers of small fragments. Because of these morphological changes mitochondria are now known to be very dynamic.The importance of frequent mitochondrial fission and fusion events for cell survival was also not fully appreciated until fairly recently. Obvious reasons, such as accommodating cell growth, cell division, and the redistribution of mitochondria during differentiation, did not fully explain why mitochondria fuse nor did they explain the high frequencies of these occurrences. However, in more recent years, the biological relevance of these phenomena has become clear with the discovery of human diseases that are caused by mutations in fission and fusion proteins and the discovery of numerous connections with apoptosis and mitophagy (Westermann 2010; Chan 2012; Nunnari and Suomalainen 2012; Youle and van der Bliek 2012). Mitochondrial fission and fusion are now considered cornerstones for cell survival because of their contributions to health and disease.