Fernández-Ayala, D.J.M., Jiménez-Gancedo, S., Guerra, I., Hernández-Camacho, J.D., Neto, M., Scialo, F., Astillero-López, V., Cortés-Rodríguez, A.B., Santos-Ocaña, C., Rodríguez-Aguilera, J.C., Casares, F., Sanz, A., López-Lluch, G., Navas, P. (2025). Modelling the human coenzyme Q deficiency in Drosophila melanogaster.  Free Radical Biol. Med. 230(): 95--111.

FBrf0261808

Research paper

The interference of the expression of each of the genes involved in the synthesis of coenzyme Q (CoQ) in Drosophila melanogaster can help to understand the pathophysiology of CoQ-dependent mitochondrial diseases in humans. We have knocked-down all genes involved in the CoQ biosynthesis pathway at different temperatures to induce depletion of CoQ at different levels throughout the body and in a tissue-specific manner. The efficiency of the knockdowns was quantified by Q-RTPCR and determination of CoQ levels by HPLC-UV + ECD. We performed mitochondria purification and quantified respiratory chain activity, both mitochondrial hydrogen peroxide and superoxide production, resistance to mechanical stress and determination of life expectancy. Finally, we evaluated the effect of CoQ10 supplementation as phenotype rescue therapy. D. melanogaster presents 3 isoforms of CoQ: CoQ8, CoQ9 and CoQ10. The level of depletion depended on the efficiency of the RNAi used and is specific for each gene. The interference of some genes interrupted fly development in embryogenesis (pdss2) or during metamorphosis (pdss1, coq3, coq5, coq8 and coq10), while in other cases viable adults can be obtained (coq2, coq6 and coq7). The knockdown of coq7 accumulated intermediates of the CoQ biosynthesis pathway at all stages of development, altered electron transfer with poor assembly of mitochondrial complexes, and deregulated mitochondrial hydrogen peroxide and superoxide production. Coq7 mutant flies showed partial lethality in metamorphosis, bang sensitivity and reduced life span of surviving animals. CoQ10 supplementation rescued the coq7-mutant phenotypes. Knock-down in the imaginal disc generated gene-specific eye deformities that can be mitigated by CoQ10 supplementation. Our results indicate that interference of the CoQ biosynthesis pathway in D. melanogaster shows a great diversity of phenotypes depending on the target gene, mirroring the heterogeneity of CoQ deficiency syndrome in humans and point to why mutations in certain genes are rarely found in patients.