Methylmalonate inhibits succinate‐supported oxygen consumption by interfering with mitochondrial succinate uptake

Abstract

The effect of methylmalonate (MMA) on mitochondrial succinate oxidation has received great attention since it could present an important role in energy metabolism impairment in methylmalonic acidaemia. In the present work, we show that while millimolar concentrations of MMA inhibit succinate-supported oxygen consumption by isolated rat brain or muscle mitochondria, there is no effect when either a pool of NADH-linked substrates or N,N,N',N'-tetramethyl-p-phenylendiamine (TMPD)/ascorbate were used as electron donors. Interestingly, the inhibitory effect of MMA, but not of malonate, on succinate-supported brain mitochondrial oxygen consumption was minimized when nonselective permeabilization of mitochondrial membranes was induced by alamethicin. In addition, only a slight inhibitory effect of MMA was observed on succinate-supported oxygen consumption by inside-out submitochondrial particles. In agreement with these observations, brain mitochondrial swelling experiments indicate that MMA is an important inhibitor of succinate transport by the dicarboxylate carrier. Under our experimental conditions, there was no evidence of malonate production in MMA-treated mitochondria. We conclude that MMA inhibits succinate-supported mitochondrial oxygen consumption by interfering with the uptake of this substrate. Although succinate generated outside the mitochondria is probably not a sig-nificant contributor to mitochondrial energy generation, the physiopathological implications of MMA-induced inhibition of substrate transport by the mitochondrial dicarboxylate carrier are discussed.

Metabolite Profiling Identifies Markers of Uremia

“…45 Methylmalonate has been shown to impair succinate oxidation in isolated muscle mitochondria. 46 Maleate can sequester mitochondrial CoA and thus inhibit oxidation of other CoA-dependent substrates. 47 However, it is unclear how plasma levels of these metabolites reflect their intracellular concentrations.…”

Multiple OXPHOS Deficiency in the Liver, Kidney, Heart, and Skeletal Muscle of Patients With Methylmalonic Aciduria and Propionic Aciduria

“…Thus, the precise mechanisms underlying complication development remain unclear, even if a role of toxic metabolites is probable (21). Apart from metabolic enzyme inhibition, MA was recently shown to inhibit the mitochondrial dicarboxylate carrier in vitro (22) suggesting that it may alter the transport of various dicarboxylic acids into mitochondria including TCA cycle intermediates (23). This mechanism may thus result in further energy metabolism deficiency and contribute to the global OXPHOS deficiency in the patients' tissues.…”

GC/MS-based urinary metabolomics reveals systematic differences in metabolism and ethanol response between Sprague–Dawley and Wistar rats

“…Current work indicated clearly that Wistar rats produced higher levels of methylmalonic and succinic acid in pairs than SD rats. Mirandola et al's (2008) work demonstrated that methylmalonic acid inhibited the oxidation of succinic acid in mitochondria, and hence higher concentrations of succinic acid were excreted together with methylmalonic acid in the urines of fasting Wistar rats compared to the fasting SD rats. Additionally, it was interesting to find that ethylmalonic and methylsuccinic acids were both significantly higher in SD rats rather than Wistar rats in the fasting condition, suggesting that the SD rats probably produced higher levels of metabolites relating to ethylmalonic encephalopathy than Wistar rats (Nowaczyk et al 1998).…”