Methylmalonate inhibits succinate-supported oxygen consumption by interfering with mitochondrial succinate uptake.

Journal of Inherited Metabolic Disease
S R MirandolaRoger F Castilho

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 mitochond...Continue Reading

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Citations

Mar 19, 2011·Journal of Inherited Metabolic Disease·Joanna Clare ClothierSally-Anne Hulton
Mar 21, 2013·Journal of Inherited Metabolic Disease·Stefan KölkerJürgen G Okun
Jan 29, 2011·Journal of Bioenergetics and Biomembranes·Daniela R MeloRoger F Castilho
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Jan 24, 2021·Free Radical Biology & Medicine·Maija DambrovaMarina Makrecka-Kuka

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