OPA1 requires mitofusin 1 to promote mitochondrial fusion

TLDR

Mitochondrial fusion–fission balance is vital for organelle integrity, yet the mechanisms of fusion in mammalian cells remain largely unknown. The study aimed to determine whether the inner‑membrane protein OPA1 participates in mitochondrial fusion or fission. OPA1 drives formation of branched, elongated mitochondria through its GTPase and coiled‑coil domains, and its depletion causes fragmentation; it promotes fusion only when mitofusin 1 is present, demonstrating that OPA1 functionally requires MFN1 and revealing a distinct role for MFN1 versus MFN2.

Abstract

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.