![]() In 2004, Jody Nunnari and colleagues were able to induce, for the first time, fusion of isolated mitochondria in vitro. Moreover, the intracellular cascades that control these machineries are not well characterized yet. However, the picture is incomplete and additional components of the fusion and fission machineries certainly remain to be identified. Our knowledge of how mitochondria fuse and fragment has significantly increased over the past decade, mainly thanks to genetic studies performed in Drosophila or yeast that allowed identification of key players of these processes. Mitochondrial dynamins can be regulated by post-translational modifications, including phosphorylation, sumoylation and ubiquitination, which impact on their function and consequently on mitochondrial shape and dynamics. Mitochondrial fission relies on the cytosolic dynamin-related protein 1 (Drp1 in mammals, Dnm1 in yeast), which uses the protein Fis1 as a receptor on the mitochondrial outer membrane. It is not known how fusion of inner and outer membranes is coordinated in mammals, but in yeast a third protein of the outer membrane, Ugo1, which interacts with both Fzo1 and Mgm1, may fulfill the role of a membrane fusion coordinator. It has been demonstrated, however, that it largely depends on another dynamin-like GTPase, Opa1 (Mgm1 in yeast). The mechanism of mitochondrial inner membrane fusion is less clear. Lipid mixing of the outer membrane could be catalyzed by lipid-modifying enzymes, such as mitochondrial phospholipase D (mito-PLD). These molecules allow tethering of two organelles before fusion of the outer membrane itself occurs. For fusion, mitochondria have mitofusins (Fzo1 in yeast) on the surface of their outer membranes. The whole process relies largely on dynamin-like proteins that hydrolyze GTP. Mitochondrial fusion requires the coordinated fusion of the outer and inner membranes. An important step towards this goal has now been accomplished by Schauss and colleagues, who have set up an elegant assay allowing quantification of mitochondrial fusion in vitro. Until now, one of the limitations in the research on mitochondrial dynamics, especially in mammals, has been the lack of a precise and reliable assay to quantify mitochondrial fusion and fission. In addition, it would be useful to identify chemical compounds that could modify mitochondrial dynamics for research or therapeutic use. It is therefore important to unravel the principles of mitochondrial fusion by identifying all the components that constitute the core fusion machinery and to understand better how this machinery is controlled and integrated into cell signaling pathways. Thus, loss of mtDNA integrity and stability could be the cause of several neurodegenerative disorders that have been associated with mitochondrial fusion impairment, including the inherited diseases Charcot-Marie-Tooth type IIA and optic nerve atrophy. Consequently, all mtDNA-encoded proteins, which are core subunits of the respiratory chain, are downregulated and oxidative phosphorylation is impaired, leading to cell dysfunctions. Impairment of mitochondrial fusion leads to accumulation of mutations in the mitochondrial genome and finally to loss of mtDNA molecules by a mechanism that is still unclear. On the other hand, fusion allows the mixing of matrix contents of different mitochondria, including their genetic information. On one hand, fragmentation or fission is necessary to produce new mitochondria from a 'mother mitochondrion' or to isolate and target damaged parts of one mitochondrion for degradation by mitophagy. To function correctly, mitochondria need to be dynamic: they move, fragment and fuse continuously. In humans, each mtDNA molecule encodes 13 proteins, 2 ribosomal RNAs and 22 tRNAs. Mitochondria contain their own genome that is packaged into nucleoid-like structures containing several mitochondrial DNA (mtDNA) molecules. However, these organelles are not restricted to this unique function but fulfill a number of other tasks, including regulation of calcium homeostasis and amino acid metabolism or the citric acid and the urea cycles, and as such participate actively in life and death of cells. Mitochondria are mainly known as the 'power house' of eukaryotic cells because they are able to catalyze the production of ATP through oxidative phosphorylation. ![]()
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