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

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

doi:10.1083/jcb.201511044

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

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^*

^*Korrespondierende/r Autor/-in für diese Arbeit

67 Zitate (Scopus)

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.

Originalsprache	Englisch
Zeitschrift	Journal of Cell Biology
Jahrgang	216
Ausgabenummer	3
Seiten (von - bis)	1-14
Seitenumfang	14
ISSN	0021-9525
DOIs	https://doi.org/10.1083/jcb.201511044
Publikationsstatus	Veröffentlicht - 01.01.2017

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We thank G. Marschner, F. Rudolph, R. Goodchild, H. Bellen, J. Park, J. Chung, and the Bloomington Drosophila Stock Center. Support was provided by a Fonds Wetenschappelijk Onderzoek and European Molecular Biology Organization stipend to M. Vos (ALTF 851-2014), a European Research Council Starting and Consolidator grant to P. Verstreken (ERC-2014-CoG-646671), Fonds Wetenschappelijk Onderzoek grants (G0D3417N, G0D3317N, G088515N, and G094915N), an Interuniversitaire Attractie Pool by Federaal Wetenschapsbeleid (P7/16), the Research Fund Katholieke Universiteit Leuven, a Methusalem grant from the Flemish government, the Hercules Foundation, Opening the Future, Deutsche Forschungsgemeinschaft (KL1134/11-1), and the Vlaams Instituut voor Biotechnologie. B. De Strooper is a paid consultant for and P. Verstreken receives research funding from Janssen Pharmaceuticals. C. Klein is the recipient of a career development award from the Hermann and Lilly Schilling Foundation.

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10.1083/jcb.201511044

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Vos, M., Geens, A., Böhm, C., Deaulmerie, L., Swerts, J., Rossi, M., Craessaerts, K., Leites, E. P., Seibler, P., Rakovic, A., Lohnau, T., De Strooper, B., Fendt, S. M., Morais, V. A., Klein, C., & Verstreken, P. (2017). Cardiolipin promotes electron transport between ubiquinone and complex I to rescue PINK1 deficiency. Journal of Cell Biology, 216(3), 1-14. https://doi.org/10.1083/jcb.201511044

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title = "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.",

author = "Melissa Vos and Ann Geens and Claudia B{\"o}hm and Liesbeth Deaulmerie and Jef Swerts and Matteo Rossi and Katleen Craessaerts and Leites, \{Elvira P.\} and Philip Seibler and Aleksandar Rakovic and Thora Lohnau and \{De Strooper\}, Bart and Fendt, \{Sarah Maria\} and Morais, \{Vanessa A.\} and Christine Klein and Patrik Verstreken",

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month = jan,

day = "1",

doi = "10.1083/jcb.201511044",

language = "English",

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Vos, M, Geens, A, Böhm, C, Deaulmerie, L, Swerts, J, Rossi, M, Craessaerts, K, Leites, EP, Seibler, P , Rakovic, A, Lohnau, T, De Strooper, B, Fendt, SM, Morais, VA, Klein, C & Verstreken, P 2017, 'Cardiolipin promotes electron transport between ubiquinone and complex I to rescue PINK1 deficiency', Journal of Cell Biology, Jg. 216, Nr. 3, S. 1-14. https://doi.org/10.1083/jcb.201511044

TY - JOUR

T1 - Cardiolipin promotes electron transport between ubiquinone and complex I to rescue PINK1 deficiency

AU - Vos, Melissa

AU - Geens, Ann

AU - Böhm, Claudia

AU - Deaulmerie, Liesbeth

AU - Swerts, Jef

AU - Rossi, Matteo

AU - Craessaerts, Katleen

AU - Leites, Elvira P.

AU - Seibler, Philip

AU - Rakovic, Aleksandar

AU - Lohnau, Thora

AU - De Strooper, Bart

AU - Fendt, Sarah Maria

AU - Morais, Vanessa A.

AU - Klein, Christine

AU - Verstreken, Patrik

PY - 2017/1/1

Y1 - 2017/1/1

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85016297592

U2 - 10.1083/jcb.201511044

DO - 10.1083/jcb.201511044

M3 - Journal articles

C2 - 28137779

AN - SCOPUS:85016297592

SN - 0021-9525

VL - 216

SP - 1

EP - 14

JO - Journal of Cell Biology

JF - Journal of Cell Biology

IS - 3

ER -

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

Abstract

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