The Effect of Methylmalonic Acid Treatment on Human Neuronal Cell Coenzyme Q Status and Mitochondrial Function.

Methylmalonic acidemia is an inborn metabolic disease of propionate catabolism, biochemically characterized by accumulation of methylmalonic acid (MMA) to millimolar concentrations in tissues and body fluids. However, MMA's role in the pathophysiology of the disorder and its status as a "toxic intermediate" is unclear, despite evidence for its ability to compromise antioxidant defenses and induce mitochondrial dysfunction. Coenzyme Q (CoQ) is a prominent electron carrier in the mitochondrial respiratory chain (MRC) and a lipid-soluble antioxidant which has been reported to be deficient in patient-derived fibroblasts and renal tissue from an animal model of the disease. However, at present, it is uncertain which factors are responsible for inducing this CoQ deficiency or the effect of this deficit in CoQ status on mitochondrial function. Therefore, in this study, we investigated the potential of MMA, the principal metabolite that accumulates in methylmalonic acidemia, to induce a cellular CoQ deficiency. In view of the severe neurological presentation of patients with this condition, human neuroblastoma SH-SY5Y cells were used as a neuronal cell model for this investigation. Following treatment with pathological concentrations of MMA (>0.5 mM), we found a significant ( = 0.0087) ~75% reduction in neuronal cell CoQ status together with a significant ( = 0.0099) decrease in MRC complex II-III activity at higher concentrations (>2 mM). The deficits in neuronal CoQ status and MRC complex II-III activity were associated with a loss of cell viability. However, no significant impairment of mitochondrial membrane potential (ΔΨm) was detectable. These findings indicate the potential of pathological concentrations of MMA to induce a neuronal cell CoQ deficiency with an associated loss of MRC complex II-III activity. However, in the absence of an impairment of ΔΨm, the contribution this potential deficit in cellular CoQ status makes towards the disease pathophysiology methylmalonic acidemia has yet to be fully elucidated.