Molecular bases of Coenzyme Q deficiency and bioenergetics of development

Primary Coenzyme Q (CoQ) deficiencies are rare conditions caused by biallelic mutations in one of the COQ genes involved in its biosynthesis. They are characterized biochemically by a reduction in CoQ, a lipid essential for energy production through oxidative phosphorylation in the mitochondria. Primary CoQ deficiencies are clinically highly heterogeneous. Many patients present a neonatal debut and a fatal outcome early in life. Still, the molecular basis for the origin of the disease is largely unknown, and there is no clear genotype-phenotype correlation. This difficulty is added to the low number of identified patients.

With the idea of ​​offering an updated database of identified patients for each gene, detailing the frequency of symptoms, we have created a handy online platform for clinicians, research staff and families:
https://coenzymeqbiology.github.io/clinic-CoQ-deficiency/

In recent years we have focused our work on the study of the pathogenesis of CoQ deficiencies caused by mutations in COQ4, one of the genes involved in CoQ biosynthesis, whose function is still unknown. In 2015 we described the first five patients with pathogenic variants of this gene. Mutations in COQ4 are severe, being a lethal condition in most cases during the first weeks or months after birth.

To study these deficiencies, we use fibroblasts from patients and COQ4 knock-out cell lines generated by CRISPR/Cas9. Our latest results suggest that COQ4 could have a double function, participating in CoQ biosynthesis and being involved in the coordination of the synthesis of this molecule and the expression of the subunits of the respiratory chain encoded by mtDNA.

Currently, the regulation of CoQ biosynthesis during development and its coordination with mitochondrial biogenesis during this period is entirely unknown. To better understand the pathogenesis of the disease, we aim to investigate the regulation of CoQ biosynthesis in genetically modified cell lines and during development by creating various Danio rerio (zebrafish) models that recapitulate CoQ deficiency.

Early diagnosis is crucial, as patients can benefit from CoQ supplementation, although responsiveness is highly variable. The low bioavailability of the molecule probably limits its efficacy, so alternative treatments are being investigated. We are interested in testing the effectiveness of various ‘bypass’ treatments of the biosynthesis pathway in the zebrafish model.