A common lipid links Mfn-mediated mitochondrial fusion and SNARE-regulated exocytosis.
Fusion of vesicles into target membranes during many types of regulated exocytosis requires both SNARE-complex proteins and fusogenic lipids, such as phosphatidic acid. Mitochondrial fusion is less well understood but distinct, as it is mediated instead by the protein Mitofusin (Mfn). Here, we identify an ancestral member of the phospholipase D (PLD) superfamily of lipid-modifying enzymes that is required for mitochondrial fusion. Mitochondrial PLD (MitoPLD) targets to the external face of mitochondria and promotes trans-mitochondrial membrane adherence in a Mfn-dependent manner by hydrolysing cardiolipin to generate phosphatidic acid. These findings reveal that although mitochondrial fusion and regulated exocytic fusion are mediated by distinct sets of protein machinery, the underlying processes are unexpectedly linked by the generation of a common fusogenic lipid. Moreover, our findings suggest a novel basis for the mitochondrial fragmentation observed during apoptosis.
Choi
Seok-Yong
SY
Graduate Program in Molecular and Cellular Biology, Center for Developmental Genetics, Stony Brook University, Stony Brook, NY 11794-5140, USA.
Huang
Ping
P
Jenkins
Gary M
GM
Chan
David C
DC
Schiller
Juergen
J
Frohman
Michael A
MA
D000818:Animals; D015153:Blotting, Western; D002308:Cardiolipins / Q000378:metabolism; D019281:Dimerization; D005089:Exocytosis / Q000502:physiology*; D020558:GTP Phosphohydrolases / Q000378:metabolism / Q000502:physiology*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008561:Membrane Fusion / Q000502:physiology*; D051379:Mice; D018613:Microscopy, Confocal; D008854:Microscopy, Electron; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000502:physiology* / Q000648:ultrastructure; D024101:Mitochondrial Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D041681:NIH 3T3 Cells; D010712:Phosphatidic Acids / Q000378:metabolism*; D010739:Phospholipase D / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D050600:SNARE Proteins / Q000502:physiology*; D014162:Transfection
D002308:Cardiolipins; D024101:Mitochondrial Proteins; D010712:Phosphatidic Acids; D050600:SNARE Proteins; D049452:Green Fluorescent Proteins; D010739:Phospholipase D; D020558:GTP Phosphohydrolases; C488750:Mfn1 protein, mouse