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

Coenzyme Q10 (CoQ10) is a critical component of the mitochondrial respiratory chain. CoQ10 deficiencies cause a variety of clinical syndromes, often involving encephalopathies. The heterogeneity of clinical manifestations implies different pathomechanisms, reflecting CoQ10 involvement in several biological processes. One such process is cholesterol homeostasis, since CoQ10 is synthesized through the mevalonate pathway, which also produces cholesterol. To elucidate the role of lipid dysfunction in the pathogenesis of CoQ10 deficiency, we investigated lipid metabolism in human CoQ10 deficient iPSCs-derived neurons, and in SH-SY5Y neurons after pharmacological manipulation of the mevalonate pathway. We show that CoQ10 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 CoQ10 levels. Our results imply that CoQ10 deficiencies can induce pathology by altering lipid homeostasis and the composition of cellular membranes. These findings provide further understanding of the mechanisms underlying CoQ10 deficiency and point to potential novel therapeutic targets.