Session Information
Date: Tuesday, June 21, 2016
Session Title: Parkinson's disease: Genetics
Session Time: 12:30pm-2:00pm
Location: Exhibit Hall located in Hall B, Level 2
Objective: Test the effect of loss of FASN on Pink1 deficiency.
Background: PINK1 deficiency causes Parkinson’s disease that is based on mitochondrial defects including inefficient electron transport between Complex I and ubiquinone. Recently, an increasing body of evidence has been connecting neurodegeneration with changes in lipid homeostasis, but how these changes are related to PINK1-induced mitochondrial dysfunction is unknown.
Methods: We performed an unbiased genetic screen and found that partial genetic and pharmacological inhibition of Fatty Acid Synthase (FASN) suppressed PINK1-induced toxicity in flies, mouse cells, patient-derived fibroblasts and iPSC-derived dopaminergic neurons.
Results: Lower FASN activity in PINK1 mutants decreased palmitate levels and increased the levels of cardiolipin, a mitochondrial inner-membrane-specific lipid. Direct supplementation of cardiolipin to isolated mitochondria not only rescued the PINK1-induced Complex I defects, but also the inefficient electron transfer in specific Complex I mutants.
Conclusions: In conjunction with structural analyses, these data indicate that cardiolipin promotes electron transfer between Complex I and ubiquinone. Hence, inhibition of FASN to increase cardiolipin levels counteracts the enzymatic defects at Complex I in Parkinson’s disease and may serve as a novel therapeutic target.
To cite this abstract in AMA style:
M. Vos, A. Geens, L. Deaulmerie, J. Swerts, K. Craessaerts, P. Seibler, A. Rakovic, B. De Strooper, R. Efremov, V.A. Morais, C. Klein, P. Verstreken. Mitochondrial cardiolipin couples electron transport between ubiquinone and complex I to rescue PINK1 deficiency [abstract]. Mov Disord. 2016; 31 (suppl 2). https://www.mdsabstracts.org/abstract/mitochondrial-cardiolipin-couples-electron-transport-between-ubiquinone-and-complex-i-to-rescue-pink1-deficiency/. Accessed December 10, 2024.« Back to 2016 International Congress
MDS Abstracts - https://www.mdsabstracts.org/abstract/mitochondrial-cardiolipin-couples-electron-transport-between-ubiquinone-and-complex-i-to-rescue-pink1-deficiency/