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 - http://www.scopus.com/inward/record.url?scp=85016297592&partnerID=8YFLogxK
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 -
