Abstract
Methylmalonic acidurias are biochemically characterized by an accumulation of methylmalonic acid and alternative metabolites. An impairment of energy metabolism plays a key role in the pathophysiology of this disease, resulting in neurodegeneration of the basal ganglia and renal failure. It has become the subject of intense debates whether methylmalonic acid is the major toxin, inhibiting respiratory chain complex II. To elucidate whether methylmalonic acid is a respiratory chain inhibitor, we used spectrophotometric analysis of complex II activity in submitochondrial particles from bovine heart, radiometric analysis of 14C-labeled substrates (pyruvate, malate, succinate), and analysis of ATP production in muscle from mice. Methylmalonic acid revealed no direct effects on the respiratory chain function, i.e. on single electron transferring complexes I-IV, ATPase, and mitochondrial transporters. However, we identified a variety of variables that must be carefully controlled to avoid an artificial inhibition of complex II activity. In summary, the study verifies our hypothesis that methylmalonic acid is not the major toxic metabolite in methylmalonic acidurias. Inhibition of respiratory chain and tricarboxylic acid cycle is most likely induced by synergistically acting alternative metabolites, in particular 2-methylcitric acid, malonic acid, and propionyl-CoA.
Highlights
Methylmalonic acidurias are biochemically characterized by an accumulation of methylmalonic acid and alternative metabolites
It has been hypothesized that MMA induced inhibition of complex II, a multiprotein assembly imparted in the tricarboxylic acid cycle and the mitochondrial respiratory chain, has become a focus of interest [12]
We found no effect of propionic acid, the decarboxylation product of MMA, on complex II activity
Summary
Methylmalonic acidurias are biochemically characterized by an accumulation of methylmalonic acid and alternative metabolites. An impairment of energy metabolism plays a key role in the pathophysiology of this disease, resulting in neurodegeneration of the basal ganglia and renal failure It has become the subject of intense debates whether methylmalonic acid is the major toxin, inhibiting respiratory chain complex II. In the present study we investigated whether MMA exerted any direct effects on mitochondrial energy metabolism and have investigated in detail the susceptibility of respiratory activity measurements to distinct artifacts.
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