Dissection of the early and late events in mitocondrial fission in budding yeast

Mitochondrial fission is important for various cellular processes such as mitochondrial morphology maintenance, proper distribution of mitochondria to energy demanding regions of the cell and regulation of cell death. In yeast, mitochondrial fission requires Dnm1p, a dynamin related GTPase, Mdv1p, a soluble protein with coiled-coil and WD-repeat motifs and Fis1p, a tail-anchored integral membrane protein containing a tetratricopeptide repeat-like fold. Caf4p, a homolog of Mdv1p was recently identified as a component of the fission pathway based on its ability to interact with the other fission proteins. However, Caf4p is not strictly required for mitochondrial fission suggesting that it has a more regulatory function. Studies in yeast indicate that mitochondrial fission consists of two distinct steps: an early step during which Dnm1p and Mdv1p assemble into discrete complexes at distinct sites on the outer mitochondrial membrane. In vivo characterization of an assembly deficient Dnm1G385Dp mutant protein suggests that smaller oligomers of Dnm1p are recruited to pre-existing Fis1p-Mdv1p complexes on mitochondria where they further assemble to form multimeric complexes. This Dnm1p multimerization drives the reorganization of Mdv1p from a uniform mitochondrial distribution to punctate fission complexes that also contain Fis1p. In a later step, these fission complexes are activated, leading to division of the mitochondrial compartment. Both Mdv1p and Fis1p have been proposed to play additional roles in the postassembly activation of mitochondrial fission although the nature of these events is currently 3 unclear. Another mutant Dnm1 protein, Dnm1<super> F610L