The sequential fusion of the outer mitochondrial membrane (OMM) and inner mitochondrial membrane (IMM) is shown from left to right. Note that both OMM and IMM fusion depend on the effective hydrolysis of GTP by the respective shaping proteins to account for the effective fusion of membranes. Homotypic or heterotypic Mfn1 and Mfn2 combinations tether and dock the OMM before its effective fusion. Fusion allows the sharing of components of the OMM and the intermembrane space (IMS) from the original mitochondria into a newly elongated one. Once the OMM is fused, long forms of Opa1 (l-Opa1) capitalize on an initial tethering of the IMM followed by a docking step. The interaction of l-Opa1 and cardiolipin at opposite sites is required for effective IMM fusion, which is fostered by heterotypic interactions between l-Opa1 and short Opa1 (s-Opa1) (B) and GTP hydrolysis.101These steps may be coordinated with the initial formation of oligomers at the IMM, as reported for Opa1102and its yeast ortholog Mgm1.103,104As shown in (A), s-Mgm1/Opa1 assemble into dimers as building blocks and subsequently tetramers that grow into helical filaments to form a lattice at the IMM, facing the intermembrane space. This occurs at buds intransfrom the two fusing mitochondria and helps stabilize the curvature of the membrane at the fusion site. After fusion of the IMM (bottom right), l-Opa1 and s-Opa1 are sorted to both sides of the fused site.
