Structural Basis of Mitochondrial Tethering by Mitofusin Complexes

TLDR

Vesicle fusion requires tethering, docking, and membrane merger. Mitofusin oligomerizes through an HR2‑mediated antiparallel coiled‑coil, with transmembrane segments at opposite ends that tether adjacent mitochondria. Mitofusin is required on neighboring mitochondria to drive fusion in trans, and its HR2 domain acts as a tether that brings mitochondria into apposition before membrane merger.

Abstract

Vesicle fusion involves vesicle tethering, docking, and membrane merger. We show that mitofusin, an integral mitochondrial membrane protein, is required on adjacent mitochondria to mediate fusion, which indicates that mitofusin complexes act in trans (that is, between adjacent mitochondria). A heptad repeat region (HR2) mediates mitofusin oligomerization by assembling a dimeric, antiparallel coiled coil. The transmembrane segments are located at opposite ends of the 95 angstrom coiled coil and provide a mechanism for organelle tethering. Consistent with this proposal, truncated mitofusin, in an HR2-dependent manner, causes mitochondria to become apposed with a uniform gap. Our results suggest that HR2 functions as a mitochondrial tether before fusion.