Methylmalonyl-CoA mutase induction by cerebral ischemia and neurotoxicity of the mitochondrial toxin methylmalonic acid

Purnima Narasimhan, Robert Sklar, Matthew Murrell, Raymond A. Swanson, Frank R Sharp

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Differential screening of gerbil brain hippocampal cDNA libraries was used to search for genes expressed in ischemic, but not normal, brain. The methylmalonyl-CoA mutase (MCM) cDNA was highly expressed after ischemia and showed a 95% similarity to mouse and 91% similarity to the human MCM cDNAs. Transient global ischemia induced a fourfold increase in MCM mRNA on Northern blots from both hippocampus and whole forebrain. MCM protein exhibited a similar induction on Western blots of gerbil cerebral cortex B and 24 hr after ischemia. Treatment of primary brain astrocytes with either the branched-chain amino acid (BCAA) isoleucine or the BCAA metabolite, propionate, induced MCM mRNA fourfold. Increased concentrations of BCAAs and odd-chain fatty acids, both of which are metabolized to propionate, may contribute to inducing the MCM gene during ischemia. Methylmalonic acid, which is formed from the MCM substrate methylmalonyl-CoA and which inhibits succinate dehydrogenase(SDH), produced dose-related cell death when injected into the basal ganglia of adult rat brain. This neurotoxicity is similar to that of structurally related mitochondrial SDH inhibitors, malonate and 3- nitropropionic acid. Methylmalonic acid may contribute to neuronal injury in human conditions in which it accumulates, including MCM mutations and B12 deficiency. This study shows that methylmalonyl-CoA mutase is induced by several stresses, including ischemia, and would serve to decrease the accumulation of an endogenous cellular mitochondrial inhibitor and neurotoxin, methylmalonic acid.

Original languageEnglish (US)
Pages (from-to)7336-7346
Number of pages11
JournalJournal of Neuroscience
Volume16
Issue number22
StatePublished - Nov 15 1996
Externally publishedYes

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Methylmalonyl-CoA Mutase
Methylmalonic Acid
Brain Ischemia
Ischemia
Branched Chain Amino Acids
Succinate Dehydrogenase
Gerbillinae
Propionates
Brain
Complementary DNA
Messenger RNA
Isoleucine
Neurotoxins
Prosencephalon
Basal Ganglia
Gene Library
Astrocytes
Northern Blotting
Cerebral Cortex
Genes

Keywords

  • 3-nitropropionic acid
  • astrocytes
  • branched-chain amino acids
  • cerebral ischemia
  • excitatory amine acids
  • hypoxia
  • malonate
  • methylmalonic acid
  • methylmalonyl-CoA mutase
  • mitochondria
  • odd-chain fatty acids
  • propionate
  • stroke
  • succinate dehydrogenase
  • vitamin B

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Methylmalonyl-CoA mutase induction by cerebral ischemia and neurotoxicity of the mitochondrial toxin methylmalonic acid. / Narasimhan, Purnima; Sklar, Robert; Murrell, Matthew; Swanson, Raymond A.; Sharp, Frank R.

In: Journal of Neuroscience, Vol. 16, No. 22, 15.11.1996, p. 7336-7346.

Research output: Contribution to journalArticle

Narasimhan, Purnima ; Sklar, Robert ; Murrell, Matthew ; Swanson, Raymond A. ; Sharp, Frank R. / Methylmalonyl-CoA mutase induction by cerebral ischemia and neurotoxicity of the mitochondrial toxin methylmalonic acid. In: Journal of Neuroscience. 1996 ; Vol. 16, No. 22. pp. 7336-7346.
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