Objectives: 

Coenzyme Q (CoQ) is synthesized in mitochondria in a complex biosynthetic pathway. In mammals, the biosynthesis of CoQ involves at least 16 proteins organized in a multi-protein complex. Coq9 is one of the CoQ biosynthetic proteins but its particular function remains unknown. It is known, however, that mutations in the human COQ9 gene cause severe infantile multisystemic disease due to CoQ deficiency. But in addition to this multisystemic infantile variant, CoQ deficiency syndrome has been associated to four other distinct clinical phenotypes, all of them caused by mutations in any of the CoQ biosynthetic genes. However, a genotype-phenotype relationship has not been demonstrated. In this study, we have investigated the function of the Coq9 protein and whether the nature of the molecular defect may be related with the clinical phenotype.

Materials: 

We have generated knockin (KI) and knockout (KO) mice for the Coq9 gene. The following determinations were made in tissues from WT, Coq9 KI and Coq9 KO mice: CoQ levels by EC-HPLC; Mass Spec analysis of abnormal metabolites; western-blot analysis of CoQ biosynthetic proteins; and histopathological analysis.

Results: 

Homozygous Coq9 KI and Coq9 KO mice are normal at birth. Chromatographic and mass spectrum analyses show that both mouse models have wide spread CoQ deficiency, and accumulate an intermediate metabolite identified in the biochemical pathway of CoQ biosynthesis. Interestingly, both mice strains show significant differences in the levels of CoQ and the accumulated metabolite, as well as in the levels of some CoQ biosynthetic proteins. Moreover, homozygous Coq9 KI and Coq9 KO mice show differences in the phenotypes, mimicking in mouse two of the human clinical presentations associated to CoQ deficiency.

Conclusions: 

Our results provide new data to understand mammalian CoQ biosynthesis. Moreover, our results may establish a relationship between gene defect, biochemical characteristics and the pathophysiology of the disease.