A Common Lipid Links Mfn-mediated Mitochondrial Fusion and SNARE-regulated Exocytosis

Nat Cell Biol. 2006 Nov;8(11):1255-62. doi: 10.1038/ncb1487. Epub 2006 Oct 8.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Blotting, Western
  • Cardiolipins / metabolism
  • Dimerization
  • Exocytosis / physiology*
  • GTP Phosphohydrolases / metabolism
  • GTP Phosphohydrolases / physiology*
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • HeLa Cells
  • Humans
  • Membrane Fusion / physiology*
  • Mice
  • Microscopy, Confocal
  • Microscopy, Electron
  • Mitochondria / enzymology
  • Mitochondria / metabolism
  • Mitochondrial Membranes / physiology*
  • Mitochondrial Membranes / ultrastructure
  • Mitochondrial Proteins / chemistry
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism
  • NIH 3T3 Cells
  • Phosphatidic Acids / metabolism*
  • Phospholipase D / chemistry
  • Phospholipase D / genetics
  • Phospholipase D / metabolism
  • RNA Interference
  • SNARE Proteins / physiology*
  • Transfection

Substances

  • Cardiolipins
  • Mitochondrial Proteins
  • Phosphatidic Acids
  • SNARE Proteins
  • Green Fluorescent Proteins
  • Phospholipase D
  • GTP Phosphohydrolases
  • Mfn1 protein, mouse