Molecular basis of selective mitochondrial fusion by heterotypic action between OPA1 and cardiolipin

Nat Cell Biol. 2017 Jul;19(7):856-863. doi: 10.1038/ncb3560. Epub 2017 Jun 19.


Mitochondria are highly dynamic organelles that undergo frequent fusion and fission. Optic atrophy 1 (OPA1) is an essential GTPase protein for both mitochondrial inner membrane (IM) fusion and cristae morphology. Under mitochondria-stress conditions, membrane-anchored L-OPA1 is proteolytically cleaved to form peripheral S-OPA1, leading to the selection of damaged mitochondria for mitophagy. However, molecular details of the selective mitochondrial fusion are less well understood. Here, we showed that L-OPA1 and cardiolipin (CL) cooperate in heterotypic mitochondrial IM fusion. We reconstituted an in vitro membrane fusion reaction using purified human L-OPA1 protein expressed in silkworm, and found that L-OPA1 on one side of the membrane and CL on the other side are sufficient for fusion. GTP-independent membrane tethering through L-OPA1 and CL primes the subsequent GTP-hydrolysis-dependent fusion, which can be modulated by the presence of S-OPA1. These results unveil the most minimal intracellular membrane fusion machinery. In contrast, independent of CL, a homotypic trans-OPA1 interaction mediates membrane tethering, thereby supporting the cristae structure. Thus, multiple OPA1 functions are modulated by local CL conditions for regulation of mitochondrial morphology and quality control.

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Bombyx / enzymology
  • Bombyx / genetics
  • Cardiolipins / metabolism*
  • GTP Phosphohydrolases / chemistry
  • GTP Phosphohydrolases / genetics
  • GTP Phosphohydrolases / metabolism*
  • Gene Targeting
  • Guanosine Triphosphate / metabolism
  • HeLa Cells
  • Humans
  • Hydrolysis
  • Liposomes
  • Mitochondria / enzymology*
  • Mitochondrial Dynamics*
  • Mitochondrial Membranes / enzymology*
  • Protein Binding
  • Protein Interaction Domains and Motifs
  • RNA Interference
  • Recombinant Proteins / metabolism
  • Signal Transduction
  • Structure-Activity Relationship
  • Time Factors
  • Transfection


  • Cardiolipins
  • Liposomes
  • Recombinant Proteins
  • Guanosine Triphosphate
  • GTP Phosphohydrolases
  • OPA1 protein, human