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.