Mitofusin 2 tethers endoplasmic reticulum to mitochondria

Nature. 2008 Dec 4;456(7222):605-10. doi: 10.1038/nature07534.

Abstract

Juxtaposition between endoplasmic reticulum (ER) and mitochondria is a common structural feature, providing the physical basis for intercommunication during Ca(2+) signalling; yet, the molecular mechanisms controlling this interaction are unknown. Here we show that mitofusin 2, a mitochondrial dynamin-related protein mutated in the inherited motor neuropathy Charcot-Marie-Tooth type IIa, is enriched at the ER-mitochondria interface. Ablation or silencing of mitofusin 2 in mouse embryonic fibroblasts and HeLa cells disrupts ER morphology and loosens ER-mitochondria interactions, thereby reducing the efficiency of mitochondrial Ca(2+) uptake in response to stimuli that generate inositol-1,4,5-trisphosphate. An in vitro assay as well as genetic and biochemical evidences support a model in which mitofusin 2 on the ER bridges the two organelles by engaging in homotypic and heterotypic complexes with mitofusin 1 or 2 on the surface of mitochondria. Thus, mitofusin 2 tethers ER to mitochondria, a juxtaposition required for efficient mitochondrial Ca(2+) uptake.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / metabolism
  • Calcium Signaling
  • Charcot-Marie-Tooth Disease / genetics
  • Endoplasmic Reticulum / metabolism*
  • Fibroblasts
  • GTP Phosphohydrolases / deficiency
  • GTP Phosphohydrolases / genetics
  • GTP Phosphohydrolases / metabolism*
  • HeLa Cells
  • Humans
  • Inositol 1,4,5-Trisphosphate / metabolism
  • Membrane Proteins / deficiency
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Mitochondria / metabolism*
  • Mitochondrial Proteins / deficiency
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism*
  • Organelle Shape

Substances

  • Membrane Proteins
  • Mitochondrial Proteins
  • Inositol 1,4,5-Trisphosphate
  • GTP Phosphohydrolases
  • MFN2 protein, human
  • Mfn1 protein, mouse
  • Mfn2 protein, mouse
  • Calcium