Mitofusins and OPA1 mediate sequential steps in mitochondrial membrane fusion.
Mitochondrial fusion requires the coordinated fusion of the outer and inner membranes. Three large GTPases--OPA1 and the mitofusins Mfn1 and Mfn2--are essential for the fusion of mammalian mitochondria. OPA1 is mutated in dominant optic atrophy, a neurodegenerative disease of the optic nerve. In yeast, the OPA1 ortholog Mgm1 is required for inner membrane fusion in vitro; nevertheless, yeast lacking Mgm1 show neither outer nor inner membrane fusion in vivo, because of the tight coupling between these two processes. We find that outer membrane fusion can be readily visualized in OPA1-null mouse cells in vivo, but these events do not progress to inner membrane fusion. Similar defects are found in cells lacking prohibitins, which are required for proper OPA1 processing. In contrast, double Mfn-null cells show neither outer nor inner membrane fusion. Mitochondria in OPA1-null cells often contain multiple matrix compartments bounded together by a single outer membrane, consistent with uncoupling of outer versus inner membrane fusion. In addition, unlike mitofusins and yeast Mgm1, OPA1 is not required on adjacent mitochondria to mediate membrane fusion. These results indicate that mammalian mitofusins and OPA1 mediate distinct sequential fusion steps that are readily uncoupled, in contrast to the situation in yeast.
Song
Zhiyin
Z
Howard Hughes Medical Institute and Division of Biology, California Institute of Technology, Pasadena, CA 91125, USA.
Ghochani
Mariam
M
McCaffery
J Michael
JM
Frey
Terrence G
TG
Chan
David C
DC
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002459:Cell Fusion; D002478:Cells, Cultured; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism / Q000648:ultrastructure; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006822:Hybrid Cells; D008561:Membrane Fusion / Q000187:drug effects; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D008854:Microscopy, Electron; D051336:Mitochondrial Membranes / Q000187:drug effects / Q000502:physiology*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D011092:Polyethylene Glycols / Q000494:pharmacology
D048868:Adaptor Proteins, Signal Transducing; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; C457224:Synj2bp protein, mouse; D049452:Green Fluorescent Proteins; D011092:Polyethylene Glycols; D020558:GTP Phosphohydrolases; C470018:MFN2 protein, human; C488750:Mfn1 protein, mouse; C498809:Opa1 protein, mouse