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

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