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

  • Original Article
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Journal of Inherited Metabolic Disease

Summary

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.

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Authors and Affiliations

  1. Departamento de Patologia Clínica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas, SP 13083-887, Brazil

    S. R. Mirandola, D. R. Melo & R. F. Castilho

  2. Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil

    P. F. Schuck, G. C. Ferreira & M. Wajner

Authors
  1. S. R. Mirandola
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  2. D. R. Melo
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  3. P. F. Schuck
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  4. G. C. Ferreira
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  5. M. Wajner
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  6. R. F. Castilho
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Correspondence to R. F. Castilho.

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Communicating editor: Garry Brown

Competing interests: None declared

References to electronic databases: Methylmalonyl-CoA mutase: EC 5.4.99.2).

S.R. Mirandola and D.R. Melo contributed equally to this work. Drs. M. Wajner and R.F. Castilho share senior authorship.

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Mirandola, S.R., Melo, D.R., Schuck, P.F. et al. Methylmalonate inhibits succinate-supported oxygen consumption by interfering with mitochondrial succinate uptake. J Inherit Metab Dis 31, 44–54 (2008). https://doi.org/10.1007/s10545-007-0798-1

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  • DOI: https://doi.org/10.1007/s10545-007-0798-1

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