Survival transcriptome in the coenzyme Q10 deficiency syndrome is acquired by epigenetic modifications: a modelling study for human coenzyme Q10 deficiencies

Objectives: Coenzyme Q(10) (CoQ(10)) deficiency syndrome is a rare condition that causes mitochondrial dysfunction and includes a variety of clinical presentations as encephalomyopathy, ataxia and renal failure. First, we sought to set up what all have in common, and then investigate why CoQ(10) supplementation reverses the bioenergetics alterations in cultured cells but not all the cellular phenotypes. Design Modelling study: This work models the transcriptome of human CoQ(10) deficiency syndrome in primary fibroblast from patients and study the genetic response to CoQ(10) treatment in these cells. Setting: Four hospitals and medical centres from Spain, Italy and the USA, and two research laboratories from Spain and the USA. Participants: Primary cells were collected from patients in the above centres. Measurements: We characterised by microarray analysis the expression profile of fibroblasts from seven CoQ(10)-deficient patients (three had primary deficiency and four had a secondary form) and aged-matched controls, before and after CoQ(10) supplementation. Results were validated by Q-RT-PCR. The profile of DNA (CpG) methylation was evaluated for a subset of gene with displayed altered expression. Results: CoQ(10)-deficient fibroblasts (independently from the aetiology) showed a common transcriptomic profile that promotes cell survival by activating cell cycle and growth, cell stress responses and inhibiting cell death and immune responses. Energy production was supported mainly by glycolysis while CoQ(10) supplementation restored oxidative phosphorylation. Expression of genes involved in cell death pathways was partially restored by treatment, while genes involved in differentiation, cell cycle and growth were not affected. Stably demethylated genes were unaffected by treatment whereas we observed restored gene expression in either non-methylated genes or those with an unchanged methylation pattern. Conclusions: CoQ(10) deficiency induces a specific transcriptomic profile that promotes cell survival, which is only partially rescued by CoQ(10) supplementation.