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

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

Author information

1
VIB Center for Brain and Disease Research, 3000 Leuven, Belgium.
2
Department of Neurosciences and Leuven Research Institute for Neurodegenerative Disease, KU Leuven, 3000 Leuven, Belgium.
3
Institute of Neurogenetics, University of Luebeck, 23562 Luebeck, Germany.
4
VIB Center for Cancer Biology, 3000 Leuven, Belgium.
5
Department of Oncology and Leuven Cancer Institute, KU Leuven, 3000 Leuven, Belgium.
6
Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, 1649 Lisboa, Portugal.
7
VIB Center for Brain and Disease Research, 3000 Leuven, Belgium patrik.verstreken@kuleuven.vib.be.

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.

PMID:
28137779
PMCID:
PMC5346965
DOI:
10.1083/jcb.201511044
[Indexed for MEDLINE]
Free PMC Article

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