QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

This Article Full Text Full Text (PDF) Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (17) Citing Articles via Google Scholar Google Scholar Articles by Narasimhan, P. Articles by Sharp, F. R. Search for Related Content PubMed PubMed Citation Articles by Narasimhan, P. Articles by Sharp, F. R.

 Previous Article  |  Next Article 

Volume 16, Number 22, Issue of November 15, 1996 pp. 7336-7346
Copyright ©1996 Society for Neuroscience

Methylmalonyl-CoA Mutase Induction by Cerebral Ischemia and Neurotoxicity of the Mitochondrial Toxin Methylmalonic Acid

Received June 17, 1996; revised Aug. 26, 1996; accepted Aug. 29, 1996.

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

Department of Neurology, University of California, San Francisco, San Francisco, California 94143, and Department of Veterans Affairs Medical Center, San Francisco, California 94121

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 8 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.

Key words: methylmalonic acid; methylmalonyl-CoA mutase; branched-chain amino acids; odd-chain fatty acids; propionate; cerebral ischemia; stroke; excitatory amino acids; vitamin B₁₂; astrocytes; 3-nitropropionic acid; succinate dehydrogenase; malonate; hypoxia; mitochondria

This article has been cited by other articles:

				T. Guttuso, M. P. McDermott, H. Su, and K. Kieburtz Effects of L-Isoleucine and L-Valine on Hot Flushes and Serum Homocysteine: A Randomized Controlled Trial Obstet. Gynecol., July 1, 2008; 112(1): 109 - 115. [Abstract] [Full Text] [PDF]

				S. Kolker, M. Schwab, F. Horster, S. Sauer, A. Hinz, N. I. Wolf, E. Mayatepek, G. F. Hoffmann, J. A. M. Smeitink, and J. G. Okun Methylmalonic Acid, a Biochemical Hallmark of Methylmalonic Acidurias but No Inhibitor of Mitochondrial Respiratory Chain J. Biol. Chem., November 28, 2003; 278(48): 47388 - 47393. [Abstract] [Full Text] [PDF]

				J. G. Okun, F. Horster, L. M. Farkas, P. Feyh, A. Hinz, S. Sauer, G. F. Hoffmann, K. Unsicker, E. Mayatepek, and S. Kolker Neurodegeneration in Methylmalonic Aciduria Involves Inhibition of Complex II and the Tricarboxylic Acid Cycle, and Synergistically Acting Excitotoxicity J. Biol. Chem., April 19, 2002; 277(17): 14674 - 14680. [Abstract] [Full Text] [PDF]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help