Control of mitochondrial morphology by a human mitofusin

TLDR

Mitochondrial size and arrangement change during differentiation and disease, yet the mechanisms of fusion, fission, and morphogenesis in mammals are unclear, though mitofusins Mfn1 and Mfn2—homologs of Drosophila Fzo—associate with mitochondria and can alter their morphology when overexpressed. We identified two human mitofusin genes (Mfn1 and Mfn2) that mediate mitochondrial fusion; a bipartite transmembrane domain targets Mfn2 to mitochondria, and its GTPase domain is required for forming long filaments and networks, especially when co‑expressed with a dominant‑negative Drp1 mutant, indicating that mitofusins and dynamin‑related GTPases have opposing roles in mammalian mitochondrial fusion and fission.

Abstract

ABSTRACT Although changes in mitochondrial size and arrangement accompany both cellular differentiation and human disease, the mechanisms that mediate mitochondrial fusion, fission and morphogenesis in mammalian cells are not understood. We have identified two human genes encoding potential mediators of mitochondrial fusion. The mitofusins (Mfn1 and Mfn2) are homologs of the Drosophila protein fuzzy onion (Fzo) that associate with mitochondria and alter mitochondrial morphology when expressed by transient transfection in tissue culture cells. An internal region including a predicted bipartite transmembrane domain (TM) is sufficient to target Mfn2 to mitochondria and requires hydrophobic residues within the TM. Co-expression of Mfn2 with a dominant interfering mutant dynamin-related protein (Drp1K38A) proposed to block mitochondrial fission resulted in long mitochondrial filaments and networks. Formation of mitochondrial filaments and networks required a wild-type Mfn2 GTPase domain, suggesting that the Mfn2 GTPase regulates or mediates mitochondrial fusion and that mitofusins and dynamin related GTPases play opposing roles in mitochondrial fusion and fission in mammals, as in yeast.