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

Abstract

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.

• Authors: Melissa Vos, Ann Geens, Claudia Böhm, Liesbeth Deaulmerie, Jef Swerts, Matteo Rossi, Katleen Craessaerts, Elvira P Leites, Philip Seibler, Aleksandar Rakovic, Thora Lohnau, Bart De Strooper, Sarah-Maria Fendt, Vanessa A Morais, Christine Klein, Patrik Verstreken
• Journal: The Journal of cell biology (J Cell Biol) Vol. 216 Issue 3 Pg. 695-708 (03 06 2017) ISSN: 1540-8140 [Electronic] United States
• PMID: 28137779 (Publication Type: Journal Article)
• Copyright: © 2017 Vos et al.

Chemical References

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

Topics

• 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, metabolism)
• Ubiquinone (metabolism)