Coenzyme Q (CoQ), also known as ubiquinone, is a lipidic molecule composed by a redox-active polar head and a polyisoprenoid chain. In the mitochondria, it shuttles electrons from complexes I and II to complex III at the electron transport chain (ETC), enabling the oxidative phosphorylation. It also feeds the ETC after receiving electrons from many other dehydrogenases and in the plasma membrane it inhibits ferroptosis. In humans, CoQ biosynthesis involves -at least- 11 proteins (COQ proteins) that act sequentially modifying the 4-hydroxy benzoic acid, the precursor of the CoQ polar head, to produce the final form of the molecule. Decrease in CoQ biosynthesis due to defects in the COQ genes cause a clinically heterogenous rare condition known as primary CoQ deficiency, characterised by a wide range of clinical manifestations, onset age and severity. A clear genotype-phenotype association is still elusive. We hypothesize that the disease unfolding due to defects in specific COQ genes could be different during development and would determine severity, the age of onset and the affected tissues. Modelling rare diseases is a promising approach to overcome the lack of epidemiological studies. That is why we have generated CRISPR-RfxCas13d knockdown and CRISPR-Cas9 loss-of-function Danio rerio (zebrafish) mutant models defective in coq4 and coq6 genes as a paradigm of genes showing a divergent clinical set of manifestations and severity. Our work will contribute to closing the gap in the knowledge of the regulation of CoQ biosynthesis during development and its coordination with mitochondrial biogenesis. The functional and physiological characterisation of the animals will help to better understand the disease triggered by coq4 and coq6 defects. Furthermore, the models have eventually the potential to serve as drug screening platforms for preclinical assays.

Trabajo presentado en el 11th International Meeting on Mitochondrial Pathology, celebrado en Bolonia (Italia) del 11 al 15 de junio de 2023.

Peer reviewed