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Cell biology and Biotechnology

Gloria Brea Calvo
Título del nuevo grupo de investigación
Gloria Brea Calvo
Researcher associated to Dr Plácido Navas Lloret. UPO

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Summary

Coenzyme Q (CoQ) deficiencies are a group of rare diseases characterized by reduced levels of this molecule, a lipid that is essential for the production of energy through oxidative phosphorylation in the mitochondria. In the electron transport chain, CoQ is an link that transfers electrons from complexes I or II to III. In addition, it receives electrons from other dehydrogenases, thus participating in very varied functions such as the synthesis of pyrimidines or the metabolism of sulfuric acid.

CoQ is synthesized endogenously by a group of 12 genes, at least in yeast, where most of the work has been done. In humans, orthologs have been identified for almost all of these genes (COQ genes), although we still do not know the function of some of them. Biosynthesis begins extramitochondrially through the mevalonate pathway, which is common to the synthesis of cholesterol and dolichol, and from tyrosine or phenylalanine which are precursors of the head. Once the head and tail are joined, it undergoes a series of sequential modifications. In yeast, the existence of a biosynthetic complex in the inner mitochondrial membrane has been established, but its existence and its regulation have not yet been fully demonstrated in humans.

Deficiencies of CoQ caused by mutations in the COQ genes are known as primary deficiencies. Other pathologies not directly related to mutations in these genes can also show decreases in CoQ levels and these are called secondary deficiencies.

Primary CoQ deficiencies are characterized by a wide variety of symptoms, making it very difficult to establish the genotype-phenotype correlation.
In the knowledge of pathology, this difficulty is added to the low number of patients identified.

We are interested in the knowledge of the function and pathogenesis of mutations in COQ4, one of the genes involved in CoQ biosynthesis, whose function is still unknown. In 2015 we described the first 5 patients with pathogenic variants of this gene and, since then, 7 more patients have been published. Mutations in COQ4 are especially serious, being a lethal pathology in most cases in the first hours or weeks after birth.

To study these deficiencies we have patient fibroblasts and cell lines knock out in COQ4 generated by CRSPR/Cas9. Our latest results indicate that COQ4 could have a double function related, on the one hand, with the synthesis of CoQ and on the other hand with the coordination of the synthesis of this molecule and the expression of the subunits of the respiratory chain encoded by mitochondrial DNA.