A fuzzy mitochondrial fusion apparatus comes into focus

Key Points Homologues of the large fuzzy onions (Fzo) GTPase are required for mitochondrial fusion in flies, budding yeast, mice and humans. The topology of the Fzo protein in the outer mitochondrial membrane is identical in budding yeast and in mammalian cells, which indicates that Fzo's role in mitochondrial fusion has probably remained intact throughout evolution. The mitochondrial fusion apparatus in both mammalian cells and budding yeast is sensitive to high levels of Fzo expression. Yeast cells express a protein that is known as Mdm30, which regulates the steady-state level of Fzo protein. Fzo homologues contain several predicted coiled-coil domains, a GTPase domain and an intermembrane space loop. Mutations in the GTPase domains of Fzo homologues in flies, budding yeast, mice and humans disrupt mitochondrial fusion, which indicates that GTP binding and/or GTP hydrolysis by Fzo proteins are required for mitochondrial fusion. Studies of coiled-coil domains in mammalian cells and of the intermembrane space loop in yeast cells indicate that these domains also have important roles in mitochondrial fusion. Two other molecules — the dynamin-related, intermembrane-space Mgm1 GTPase and the new outer-membrane protein Ugo1 — are clearly required for mitochondrial fusion in yeast. Mgm1 and Ugo1 form a physical complex with Fzo1. Several putative mitochondrial fusion molecules were isolated in a recent genetic screen for mitochondrial morphology mutants and must now be tested in mitochondrial fusion assays. Another recent study uncovered a family of evolutionarily conserved atypical Rho GTPases, which are known as Miro proteins, that affect mitochondrial morphology in human cells. Clearly, Fzo proteins are required for mitochondrial fusion. However, the mechanistic role of these transmembrane GTPases in mitochondrial tethering and lipid mixing remains elusive. We present a model for mitochondrial fusion that builds on conserved mechanistic strategies for viral and SNARE-mediated fusion pathways. Membrane fusion is fundamental to eukaryotic life. Unlike the predominant intracellular fusion machineries that fuse compartments bounded by a single membrane, the mitochondrial fusion machinery must sequentially fuse the outer and inner mitochondrial membranes. These coordinated fusion events rely on a transmembrane GTPase that is known as fuzzy onions or Fzo. Recent studies have revealed that Fzo has an evolutionarily conserved role in mitochondrial fusion, and they t