Coenzyme Q10 deficiency disrupts lipid metabolism by altering cholesterol homeostasis in neurons

Coenzyme Q 10 (CoQ 10 ) is a critical component of the mitochondrial respiratory chain. CoQ 10 deficiencies often cause a variety of clinical syndromes, often involving encephalopathies. The heterogeneity of clinical manifestations implies different pathomechanisms, reflecting CoQ 10 involvement in several biological processes. One such process is cholesterol homeostasis, since CoQ 10 is synthesized through the mevalonate pathway, which also produces cholesterol. To elucidate the role of lipid dysfunction in the pathogenesis of CoQ 10 deficiency, we investigated lipid metabolism in human CoQ 10 deficient iPSCs-derived neurons, and in SH-SY5Y neurons after pharmacological manipulation of the mevalonate pathway. We show that CoQ 10 deficiency causes alterations in cholesterol homeostasis, fatty acids oxidation, phospholipids and sphingolipids synthesis in neurons. These alterations depend on the molecular defect, and on the residual CoQ 10 levels. Our results imply that CoQ 10 deficiencies can induce pathology by altering lipid homeostasis and the composition of cellular membranes. These findings provide further understanding of the mechanisms underlying CoQ 10 deficiency and point to potential novel therapeutic targets. • CoQ 10 deficiency alters lipid metabolism in neurons. • Lipid dysfunction in CoQ 10 deficiency is mediated by cholesterol alterations. • Cholesterol abnormalities depend on CoQ 10 levels rather than the molecular defect. • Imbalance in lipid membrane might affect neuronal morphology and function.