Cardiolipin promotes electron transport between ubiquinone and complex I to rescue PINK1 deficiency

J Cell Biol. 2017 Mar 6;216(3):695-708. doi: 10.1083/jcb.201511044. Epub 2017 Jan 30.


PINK1 is mutated in Parkinson's disease (PD), and mutations cause mitochondrial defects that include inefficient electron transport between complex I and ubiquinone. Neurodegeneration is also connected to changes in lipid homeostasis, but how these are related to PINK1-induced mitochondrial dysfunction is unknown. Based on an unbiased genetic screen, we found that partial genetic and pharmacological inhibition of fatty acid synthase (FASN) suppresses toxicity induced by PINK1 deficiency in flies, mouse cells, patient-derived fibroblasts, and induced pluripotent stem cell-derived dopaminergic neurons. Lower FASN activity in PINK1 mutants decreases palmitate levels and increases the levels of cardiolipin (CL), a mitochondrial inner membrane-specific lipid. Direct supplementation of CL to isolated mitochondria not only rescues the PINK1-induced complex I defects but also rescues the inefficient electron transfer between complex I and ubiquinone in specific mutants. Our data indicate that genetic or pharmacologic inhibition of FASN to increase CL levels bypasses the enzymatic defects at complex I in a PD model.

MeSH terms

  • Animals
  • Cardiolipins / metabolism*
  • Cell Line, Tumor
  • Dopaminergic Neurons / metabolism
  • Electron Transport / physiology*
  • Electron Transport Complex I / metabolism*
  • Fatty Acid Synthases / metabolism
  • Fibroblasts / metabolism
  • HeLa Cells
  • Humans
  • Induced Pluripotent Stem Cells / metabolism
  • Mice
  • Mitochondria / metabolism
  • Mutation / genetics
  • Protein Kinases / genetics
  • Protein Kinases / metabolism*
  • Ubiquinone / metabolism*


  • Cardiolipins
  • Ubiquinone
  • Fatty Acid Synthases
  • Protein Kinases
  • Electron Transport Complex I