Key proteins required for mitochondrial fusion include: large GTPases, Mfn1 and Mfn2 (homologues of yeast Fzo1p) [12
], and OPA1 (Optic Atrophy protein 1, homologue of yeast Mgm1p) [14
]. These proteins can physically interact [17
] and appear to act in concert in mitochondrial fusion. The OMM-localized Mfn1 and Mfn2 are required for the initial tethering of fusing mitochondria [18
]. The second step of mitochondrial fusion likely requires the physical interaction between OPA1 and the two IMMs to be fused. These interactions are probably stabilized by a pool of soluble OPA1 present in the intermembrane space [20
]. This process depends on the energy released by the hydrolysis of GTP [21
]. Although fusions of the OMM and IMM are normally highly synchronized, they can be uncoupled. For example in mammalian cells, dissipation of mitochondrial membrane potential (ΔΨm
) appears to selectively inhibit IMM fusion [22
]. This, in addition to the recent identification of yeast mitochondrial fusion intermediates in vitro
], suggests that the OMM and IMM may fuse in successive and independent reactions.
On the other hand, mitochondrial fission requires the mobilization from the cytosol of a large dynamin related protein, Drp1 (Dnm1p in yeast) (). Drp1 is essential for mitochondrial division in all tested phyla [11
]. Drp1 traffics between the cytosol and the mitochondria [24
] where it forms submitochondrial foci, some of which develop into active mitochondrial fission sites [23
] (). It has been proposed that Fis1, an OMM-associated protein required for fission of mitochondria, recruits Drp1 to the OMM and facilitates Drp1-dependent scission of the OMM. The mechanism by which Fis1 and Drp1 interaction initiate mitochondrial division in mammalian cells is not clear. It is not known whether Drp1 acts as a signaling molecule or whether this protein can induce mitochondrial scission directly. In vitro
], as well as the studies of Dnm1p, revealed that like dynamin, Dnm1p could form the OMM-associated large polymers that can wrap spirally around the mitochondrial tubule [27
]. These spirals are believed to mediate the OMM deformations leading to the terminal fission of mitochondrial membranes. The mechanism of mitochondrial constriction in mammalian cells, and whether this process depends on Drp1 are not known. In addition, the regulation of IMM scission, including proteins participating in this process, as well as mechanisms synchronizing scissions of the IMM and the OMM are currently unknown.
The large GTPase, Drp1 mediates division of mitochondria
The unique complexity of fusion and fission of a two-membrane system such as mitochondria entails, in addition to aforementioned key fusion and fission proteins, a number of additional factors, including lipid-modifying or structural proteins that are required for the progression of these processes. Furthermore, the coordination of mitochondrial dynamics and structure with the overall function of the cell, as well as mitochondrial response to specific extramitochondrial signals would also require a number of additional factors. The current status on the regulation of core mitochondrial fusion and fission machineries is reviewed below.