Structural Basis of Mitochondrial Tethering by Mitofusin Complexes

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.

Loss of sirtuin 1 and mitofusin 2 contributes to enhanced ischemia/reperfusion injury in aged livers

“…MFN2 comprises a bipartite transmembrane region and a highly conserved heptad repeat (HR) domain that contains a helical, coiled‐coil structure near the C‐terminus (Figure 6a). Crystallographic analysis revealed that MFN2 can form either homotypic or heterotypic dimer through HR‐mediated interaction (Koshiba et al., 2004). As changes in pH profoundly impact the hydrogen bonds and electrostatic properties that are essential to the maintenance of stable protein complexes, acidic pH could induce a conformational change, leading to weakening the MFN1‐MFN2 or MFN2‐MFN2 interaction.…”

Interspecies mitochondrial fusion between mouse and human mitochondria is rapid and efficient

“…A detailed molecular understanding of mitochondrial fusion is emerging (Meeusen et al, 2004;Koshiba et al, 2004). Mitochondrial fusion proteins, which are nuclear-encoded, are associated with both the outer and inner mitochondrial membranes.…”

“…In mice and other mammals, homologs of two of these proteins have been identified: mitofusin 1 (Mfn1) and mitofusin 2 (Mfn2) are homologs of Fzo1, and Opa1 is homologous to Mgm1 Cipolat et al, 2004). The carboxy-terminal cytosolic domains of Fzo1 or mitofusin proteins have been shown to form homotypic antiparallel dimers (Koshiba et al, 2004;Pfanner et al, 2004). Binding in trans between the Fzo1 or mitofusin proteins in adjacent mitochondria provides the mechanism for the first step of the fusion process (i.e., tethering).…”

Mitofusins ‘bridge’ the gap between oxidative stress and mitochondrial hyperfusion

“…The heptad repeats are involved in membrane-tethering events, and structural analysis of a HR2 dimer revealed that it forms an antiparallel coiledcoil [5]. When the authors added nonhydrolysable GTP to their in vitro assay, the GSSG-mediated fusion was blocked.…”