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Methylmalonate impairs mitochondrial respiration supported by NADH-linked substrates: involvement of mitochondrial

Daniela R Melo1, Sandra R Mirandola, Nilson A Assunção

  • 1Departamento de Patologia Clínica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas, São Paulo, Brazil.

Journal of Neuroscience Research
|April 11, 2012
PubMed

Insights

Methylmalonate (MMA) accumulation impairs mitochondrial function in methylmalonic acidemia by inhibiting key enzymes and reducing substrate availability, particularly affecting glutamate metabolism. Chronic in vivo MMA exposure did not cause lasting mitochondrial damage.

Area of Science:

  • Biochemistry
  • Neuroscience
  • Mitochondrial Biology

Background:

  • Methylmalonic acidemia is linked to neurodegeneration.
  • Methylmalonate (MMA) accumulation is a suspected cause via impaired mitochondrial oxidative metabolism.

Purpose of the Study:

  • To investigate the effects of MMA on mitochondrial respiration and metabolism.
  • To determine the mechanisms by which MMA affects mitochondrial function in the brain.

Main Methods:

  • Isolated rat brain mitochondria were used to measure oxygen consumption with various NADH-linked substrates.
  • Enzyme activities (glutamate dehydrogenase, aspartate aminotransferase, α-ketoglutarate dehydrogenase) were assessed.
  • Glutamate and α-ketoglutarate transport were measured.
  • In vivo studies involved chronic MMA administration to rats.

Main Results:

  • MMA (1-10 mM) significantly inhibited respiration supported by glutamate or glutamate plus malate.
  • MMA significantly inhibited α-ketoglutarate dehydrogenase (K(i) = 3.65 mM).
  • MMA/α-ketoglutarate exchange reduced mitochondrial α-ketoglutarate levels.
  • Chronic in vivo MMA treatment did not result in permanent mitochondrial respiratory defects.

Conclusions:

  • MMA inhibits mitochondrial oxidative metabolism through enzyme inhibition and reduced substrate availability.
  • Specific inhibition of α-ketoglutarate dehydrogenase and substrate depletion contribute to impaired respiration.
  • The neurodegeneration in methylmalonic acidemia may stem from these acute mitochondrial effects, not permanent damage.

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