Mitochondrial cardiolipin couples electron transport between ubiquinone and complex I to rescue PINK1 deficiency

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.status: publishe