How mitochondria fuse

Abstract

Mitochondrial fusion is unique; no paradigm exists to explain how two sets of compositionally distinct membranes become coordinately fused. Genetic approaches coupled with in vivo observations of mitochondrial dynamics and morphology have identified the machinery involved in mitochondrial fusion but these approaches alone yield limited mechanistic insight. The recent recapitulation of mitochondrial fusion in vitro has allowed the fusion process to be dissected into two mechanistically distinct, resolvable steps: outer membrane fusion and inner membrane fusion. Outer membrane fusion requires homotypic trans interactions of the ancient dynamin-related GTPase Fzo1, the proton-gradient component of the inner membrane electrical potential, and low levels of GTP hydrolysis. Fusion of inner membranes requires the electrical component (Deltapsi) of the inner membrane electrical potential and elevated levels of GTP hydrolysis. Regulation of mitochondrial fusion is likely to involve transcript processing in mammalian cells as well as variation in the level of fusion proteins in a given cell; slight changes in the electrical potential of the inner membrane may also serve to fine-tune fusion rates. Mitochondrial fusion components also serve to protect cells against apoptosis through mechanisms that are largely unknown. Resolving the mechanism of mitochondrial fusion will provide insight into the role of fusion components in apoptosis.