Methylmalonic Acid, a Biochemical Hallmark of Methylmalonic Acidurias but No Inhibitor of Mitochondrial Respiratory Chain

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 14 C-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.

Metabolomics Identifies Perturbations in Human Disorders of Propionate Metabolism

“…Patients with complete apoenzyme deficiency (mut 0 ) typically present early in life with severe symptoms, including high mortality and neurologic impairment, whereas those with partial apoenzyme deficiency (mut -) typically have less severe symptoms. Abnormalities in the processing of vitamin B 12 to the active coenzyme adenosylcobalamin (cblA, B, C, and D) are amenable to treatment with B 12 supplementation, and present later with the best prognosis (9 ). Within each of these groups there is substantial variability in disease severity and prognosis, for which there is no biomarker.…”

“…PA results from a defect in the enzyme propionyl-CoA carboxylase, which catalyzes the biotin-dependent conversion of propionyl-CoA to methylmalonyl-CoA (8 ). MMA results from deficiency of the immediately downstream enzyme methylmalonyl-CoA mutase, which catalyzes the vitamin B 12 -dependent conversion of methylmalonylCoA to succinyl-CoA (Fig. 2).…”

Expression of Proinflammatory Factors in Renal Cortex Induced by Methylmalonic Acid

“…It has been demonstrated that accumulating organic acids and CoA esters play a central role in the neuropathogenesis of methylmalonic acidemia. In particular, propionyl-CoA and methylcitric acid synergistically inhibit enzymes of the tricarboxylic acid cycle, pyruvate dehydrogenase complex, and respiratory chain, 16 whereas it has been suggested that MMA competes with the mitochondrial import of succinate. 17 In contrast to the neuropathogenesis, mechanisms underlying chronic renal failure have not yet been extensively studied.…”

“…25 Emerging evidence points to a disturbance of cellular energy metabolism by MMA and related metabolites. 16 As the tubule cell has high energy requirements and TI nephritis can also be found in patients with primary mitochondrial disorders, 26 this might be a first physiopathological link. It is worth mentioning that although the differences we observed in the expression of SIRT1 between control and model rats were not significant, it is quite likely that they would have reached significance if the number of experiments performed or the time of exposure to the acid had been greater.…”

Biodegradable mixed MPEG-SS-2SA/TPGS micelles for triggered intracellular release of paclitaxel and reversing multidrug resistance

“…[51][52][53] The dysfunction of complex II can cause the leakage of electrons during the transfer in the complex II and the activation of calcium channel, resulting in the mitochondria and intracellular overload of calcium and eventually leading to the disappearance of the mitochondrial membrane potential, which is one of the mechanisms of mitochondrial dysfunction. 54,55 Micelles containing TPGS significantly inhibited the activity of mitochondrial respiratory complex II, and the inhibition effect gradually increased over the incubation time ( Figure 6). However, the MPEG-SS-2A micelles barely affected the activity of complex II.…”