The regulated equilibrium between mitochondrial fusion and fission is essential to maintain integrity of the organelle. Mechanisms of mitochondrial fusion are largely uncharacterized in mammalian cells. It is unclear whether OPA1, a dynamin-related protein of the inner membrane mutated in autosomal dominant optic atrophy, participates in fusion or fission. OPA1 promoted the formation of a branched network of elongated mitochondria, requiring the integrity of both its GTPase and C-terminal coiled-coil domain. Stable reduction of OPA1 levels by RNA interference resulted in small, fragmented, and scattered mitochondria. Levels of OPA1 did not affect mitochondrial docking, but they correlated with the extent of fusion as measured by polyethylene glycol mitochondrial fusion assays. A genetic analysis proved that OPA1 was unable to tubulate and fuse mitochondria lacking the outer membrane mitofusin 1 but not mitofusin 2. Our data show that OPA1 functionally requires mitofusin 1 to regulate mitochondrial fusion and reveal a specific functional difference between mitofusin 1 and 2. M itochondria are crucial organelles for life and death of the cell: they produce most cellular ATP, shape cytosolic Ca 2ϩ transients, and integrate diverse apoptotic stimuli by releasing protein cofactors needed for the efficient activation of effector caspases (1, 2). Such a functional versatility is matched by a complex structural organization. The mitochondrial cristae have been identified as a separate compartment connected to the thin intermembrane space by narrow tubular junctions (3), which may generate gradients of ions and small molecules along the cristae (4) and are responsible for the segregation of cytochrome c in the cristae compartment (5, 6). In the cytosol of certain cell types, mitochondria are organized in a network of individual organelles that dynamically fuse and divide (7,8), generating functional mitochondrial cables. This organization allows stimuli hitting one end of the mitochondrial wire to be readily transmitted to distal components of the net (9), a useful property in large cells such as cardiomyocytes (10). On the other hand, mitochondria can also behave as individual units in other cell types, such as pancreatic beta cells (11). Mitochondrial shape is not static, because during mitosis, mitochondria divide and partition into daughter cells (12). Major changes of mitochondrial morphology have been described during apoptosis, with fragmentation of the mitochondrial network, cristae fusion, and enlargement of cristae junctions (6, 13).Dynamic control of mitochondrial structure is performed by a growing set of ''mitochondria-shaping'' proteins that include both pro-fusion and pro-fission members, several of which have been identified in budding yeast (14). Fission of yeast mitochondria is accomplished by the recruitment of the dynamin-related large GTPase Dnm1p to the outer membrane, where it forms a complex with the adapter Mdv1p and the integral membrane protein . Fusion involves proteins localized at both the o...
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