Objectives: 

Coenzyme Q (CoQ), is a well-known component of the mitochondrial respiratory chain and an important antioxidant. Primary CoQ deficiency is an autosomal recessive syndrome caused by defects of the ubiquinone biosynthesis pathway. This disorder manifests clinically with five major phenotypes: 1) encephalomyopathy 2) severe infantile multisystem disorder 3) ataxic syndrome with cerebellar atrophy 4) isolated myopathy and ⁵ nephrotic syndrome. This clinical heterogeneity suggests that different pathogenic mechanisms may be involved in the pathophysiology of the disease. Thus, we hypothesize that CoQ deficiency may cause tissue-specific differences on bioenergetics defect, oxidative stress and apoptosis, which may explain, at least in part, the phenotypic variability of CoQ deficiency syndrome.

Materials: 

We have generated a genetically modified mouse model with wide spread CoQ deficiency. We have quantified the ATP levels and ATP/ADP in different tissues of CoQ-deficient mice by UV-HPLC. Mitochondrial respiration was measured by high-resolution respirometry. Oxidative stress markers were determined by the measurement of the activity of the Manganese-dependent Superoxide Dismutase (SOD) and the evaluation of the gluthatione system. Apoptosis studies were performed through the quantification of pro- and anti-apoptotic proteins by western blotting.

Results: 

CoQ deficient mice develop encephalopathy at 3 m.o. At this age ATP levels and ATP/ADP are significantly decreased in the brain but not in other tissues. These results are consistent with the dissimilar depletion of respiration through the different CoQ-dependent complexes. Additionally, the differences in the oxidative stress and apoptotic markers support this brain pathology.

Conclusions: 

Our results provide the basis to understand the pathophysiological consequences of CoQ deficiency and will furnish novel insights that may be relevant to clarify how CoQ deficiency cause these heterogenic clinical phenotypes.