Abstract
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 Q10 (CoQ10) 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 CoQ10 deficiency or the effect of this deficit in CoQ10 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 CoQ10 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 (p = 0.0087) ~75% reduction in neuronal cell CoQ10 status together with a significant (p = 0.0099) decrease in MRC complex II–III activity at higher concentrations (>2 mM). The deficits in neuronal CoQ10 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 CoQ10 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 CoQ10 status makes towards the disease pathophysiology methylmalonic acidemia has yet to be fully elucidated.
Highlights
Methylmalonic acidemia is an organic acidemia which clinically difficult to manage can show improvement as the result of treatment
To assess the effect of methylmalonic acid (MMA) treatment on the neuronal MMA status, and to confirm that this metabolite was taken up by the SH-SY5Y cells, the intracellular concentration of MMA was analysed by liquid chromatography–tandem mass spectrometry (LC-MS) following 7 days of culture with exogenous MMA (2 and 5 mM)
0.5 mM MMA induced an approximate 75% decrease in cellular Coenzyme Q10 (CoQ10) status, the treatment of the SH-SY5Y cells with higher concentrations of MMA (1, 2, 5 mM; Figure 1a) did not result in a further deficit in cellular CoQ10 status which was decreased to a similar level following all treatments
Summary
Methylmalonic acidemia is an organic acidemia which clinically difficult to manage can show improvement as the result of treatment. In view of the dependence of MRC complex II–III activity upon endogenous coenzyme Q10 (CoQ10), the decrease in the activity of this enzyme following MMA exposure may have resulted from a deficit in CoQ10 status induced by this metabolite [20]. This possibility was not further investigated in the study by Brusque et al (2002) [19]. In view of the severe neurological presentation of patients with methylmalonic acidemia [13], human neuroblastoma SH-SY5Y cells were chosen as the appropriate cell line for this investigation
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