title: Methylmalonyl-CoA mutase induction by cerebral ischemia and neurotoxicity of the mitochondrial toxin methylmalonic acid.
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 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.
authors.affiliation: Department of Neurology, University of California, San Francisco 94143, USA.
authors.forename: P
authors.initials: P
authors.lastname: Narasimhan
authors.forename: R
authors.initials: R
authors.lastname: Sklar
authors.forename: M
authors.initials: M
authors.lastname: Murrell
authors.forename: R A
authors.initials: RA
authors.lastname: Swanson
authors.forename: F R
authors.initials: FR
authors.lastname: Sharp
mesh_terms: D000818:Animals; D001479:Basal Ganglia / Q000098:blood supply / Q000166:cytology / Q000378:metabolism; D001483:Base Sequence; D015152:Blotting, Northern; D015153:Blotting, Western; D001923:Brain Chemistry / Q000502:physiology; D002545:Brain Ischemia / Q000503:physiopathology*; D016923:Cell Death / Q000187:drug effects; D018076:DNA, Complementary / Q000032:analysis; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000502:physiology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology; D005849:Gerbillinae; D007532:Isoleucine / Q000494:pharmacology; D008297:Male; D008764:Methylmalonic Acid / Q000633:toxicity*; D008765:Methylmalonyl-CoA Mutase / Q000235:genetics* / Q000378:metabolism; D008845:Microinjections; D008928:Mitochondria / Q000737:chemistry / Q000187:drug effects; D008969:Molecular Sequence Data; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D009498:Neurotoxins / Q000494:pharmacology*; D018384:Oxidative Stress / Q000502:physiology; D011422:Propionates / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D017386:Sequence Homology, Amino Acid
chemical_list: D018076:DNA, Complementary; D009498:Neurotoxins; D011422:Propionates; D012333:RNA, Messenger; D007532:Isoleucine; D008764:Methylmalonic Acid; D008765:Methylmalonyl-CoA Mutase; C029658:propionic acid