title: Cardiolipin promotes electron transport between ubiquinone and complex I to rescuePINK1deficiency.
abstract: PINK1is 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 inPINK1mutants 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 thePINK1-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.affiliation: VIB Center for Brain and Disease Research, 3000 Leuven, Belgium.|Department of Neurosciences and Leuven Research Institute for Neurodegenerative Disease, KU Leuven, 3000 Leuven, Belgium.|Institute of Neurogenetics, University of Luebeck, 23562 Luebeck, Germany.
authors.forename: Melissa
authors.identifier: 0000-0002-9883-7698
authors.initials: M
authors.lastname: Vos
authors.affiliation: VIB Center for Brain and Disease Research, 3000 Leuven, Belgium.|Department of Neurosciences and Leuven Research Institute for Neurodegenerative Disease, KU Leuven, 3000 Leuven, Belgium.
authors.forename: Ann
authors.initials: A
authors.lastname: Geens
authors.affiliation: Institute of Neurogenetics, University of Luebeck, 23562 Luebeck, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Böhm
authors.affiliation: VIB Center for Brain and Disease Research, 3000 Leuven, Belgium.|Department of Neurosciences and Leuven Research Institute for Neurodegenerative Disease, KU Leuven, 3000 Leuven, Belgium.
authors.forename: Liesbeth
authors.initials: L
authors.lastname: Deaulmerie
authors.affiliation: VIB Center for Brain and Disease Research, 3000 Leuven, Belgium.|Department of Neurosciences and Leuven Research Institute for Neurodegenerative Disease, KU Leuven, 3000 Leuven, Belgium.
authors.forename: Jef
authors.initials: J
authors.lastname: Swerts
authors.affiliation: VIB Center for Cancer Biology, 3000 Leuven, Belgium.|Department of Oncology and Leuven Cancer Institute, KU Leuven, 3000 Leuven, Belgium.
authors.forename: Matteo
authors.initials: M
authors.lastname: Rossi
authors.affiliation: VIB Center for Brain and Disease Research, 3000 Leuven, Belgium.|Department of Neurosciences and Leuven Research Institute for Neurodegenerative Disease, KU Leuven, 3000 Leuven, Belgium.
authors.forename: Katleen
authors.identifier: 0000-0001-6684-8475
authors.initials: K
authors.lastname: Craessaerts
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, 1649 Lisboa, Portugal.
authors.forename: Elvira P
authors.initials: EP
authors.lastname: Leites
authors.affiliation: Institute of Neurogenetics, University of Luebeck, 23562 Luebeck, Germany.
authors.forename: Philip
authors.initials: P
authors.lastname: Seibler
authors.affiliation: Institute of Neurogenetics, University of Luebeck, 23562 Luebeck, Germany.
authors.forename: Aleksandar
authors.identifier: 0000-0002-8127-7911
authors.initials: A
authors.lastname: Rakovic
authors.affiliation: Institute of Neurogenetics, University of Luebeck, 23562 Luebeck, Germany.
authors.forename: Thora
authors.initials: T
authors.lastname: Lohnau
authors.affiliation: VIB Center for Brain and Disease Research, 3000 Leuven, Belgium.|Department of Neurosciences and Leuven Research Institute for Neurodegenerative Disease, KU Leuven, 3000 Leuven, Belgium.
authors.forename: Bart
authors.identifier: 0000-0001-5455-5819
authors.initials: B
authors.lastname: De Strooper
authors.affiliation: VIB Center for Cancer Biology, 3000 Leuven, Belgium.|Department of Oncology and Leuven Cancer Institute, KU Leuven, 3000 Leuven, Belgium.
authors.forename: Sarah-Maria
authors.initials: SM
authors.lastname: Fendt
authors.affiliation: VIB Center for Brain and Disease Research, 3000 Leuven, Belgium.|Department of Neurosciences and Leuven Research Institute for Neurodegenerative Disease, KU Leuven, 3000 Leuven, Belgium.|Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, 1649 Lisboa, Portugal.
authors.forename: Vanessa A
authors.initials: VA
authors.lastname: Morais
authors.affiliation: Institute of Neurogenetics, University of Luebeck, 23562 Luebeck, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Klein
authors.affiliation: VIB Center for Brain and Disease Research, 3000 Leuven, Belgium patrik.verstreken@kuleuven.vib.be.|Department of Neurosciences and Leuven Research Institute for Neurodegenerative Disease, KU Leuven, 3000 Leuven, Belgium.
authors.forename: Patrik
authors.initials: P
authors.lastname: Verstreken
mesh_terms: D000818:Animals; D002308:Cardiolipins / Q000378:metabolism*; D045744:Cell Line, Tumor; D059290:Dopaminergic Neurons / Q000378:metabolism; D004579:Electron Transport / Q000502:physiology*; D042967:Electron Transport Complex I / Q000378:metabolism*; D064429:Fatty Acid Synthases / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D014451:Ubiquinone / Q000378:metabolism*
chemical_list: D002308:Cardiolipins; D014451:Ubiquinone; D064429:Fatty Acid Synthases; D011494:Protein Kinases; D042967:Electron Transport Complex I