CoQ₁₀ is a lipid molecule. Biosynthesis of CoQ₁₀ and cholesterol are linked via a common upstream pathway, specifically, the first enzyme of CoQ₁₀ biosynthesis, decaprenyl diphosphate synthase (PDSS1/PDSS2) utilizes geranylgeranyl-diphosphate (GGdP), a substrate generated by the mevalonate pathway, which is responsible for the de novo synthesis of cholesterol. Deficiency of CoQ₁₀ can be primary, due to a biosynthetic defect, or secondary to proteins not directly related to CoQ₁₀ biosynthesis. In both forms of CoQ₁₀ deficiency, there is clinical heterogeneity, but patients often present neurological conditions including Leigh syndrome and cerebellar ataxia. Phenotype variability might be due to molecular heterogenicity, multiple functions of CoQ₁₀, and/or tissue-specific mechanisms. The effects of CoQ₁₀ deficiency on lipid dysmetabolism in these diseases is unknown.

We used control and CoQ₁₀ deficient fibroblasts carrying mutations in PDSS2, COQ8A and APTX, to generate iPSCs, which were differentiated into neurons. To characterize lipid metabolism in the neurons, we performed lipidomics, transcriptional analyses, western blots, immunostaining, and biochemical and molecular assays. To characterize causal relationship between abnormal CoQ₁₀ and cholesterol metabolism, we pharmacologically manipulated the mevalonate pathway, and its CoQ₁₀ and cholesterol branches in SH-SY5Y neuronal lines.

Neurons with primary CoQ₁₀ deficiency showed significant impairment in fatty acids oxidation, sphingolipids biosynthesis, and cholesterol homeostasis, which were reproduced by inhibition of CoQ₁₀ deficiency in SH-SY5Y neurons. APTX mutant neurons, a model of secondary CoQ₁₀ deficiency, showed sphingolipids biosynthesis, and cholesterol homeostasis alterations, which were reproduced by inhibition of the mevalonate pathway in SH-SY5Y neurons.

Primary and secondary forms of CoQ₁₀ deficiency are associated with alterations in lipid metabolism including cholesterol biosynthesis in neurons.