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.