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.

Neurodegeneration in Methylmalonic Aciduria Involves Inhibition of Complex II and the Tricarboxylic Acid Cycle, and Synergistically Acting Excitotoxicity

“…Is Methylmalonate an Inhibitor of Respiratory Chain Complex II?-It has previously been reported that MMA induces neuronal damage, involving ionotropic GluRs and oxidative stress (13)(14)(15)(16)(17). These results were confirmed in the present study.…”

“…MMA induces cell damage in different neuronal culture systems (13,14). Furthermore, intrastriatal injections of MMA evokes rotational behavior, seizures, and striatal lesions in rats (15,16). MMA-induced * The costs of publication of this article were defrayed in part by the payment of page charges.…”

Methylmalonic Acid, a Biochemical Hallmark of Methylmalonic Acidurias but No Inhibitor of Mitochondrial Respiratory Chain

“…Thus, it seemed reasonable to suggest MMA as an endogenous toxic metabolite inducing neurodegenerative changes via impairment of energy metabolism (7,12). In fact, administration of MMA in vitro and in vivo induced neuronal cell damage involving ionotropic glutamate receptors and oxidative stress (13)(14)(15)(16)(17). Although two previous studies from the same group demonstrated inhibition of complex II activity by MMA (10, 11), we could not confirm this finding in a recent study (15).…”

“…It has been hypothesized that MMA induced inhibition of complex II (synonym, succinate:ubiquinone oxidoreductase), a multiprotein assembly imparted in the tricarboxylic acid cycle and the mitochondrial respiratory chain, has become a focus of interest (12). MMA induced cell damage in different neuronal culture systems (13)(14)(15) and evokes rotational behavior, seizures, and striatal lesions in rats after intrastriatal administration (16,17). MMA-induced changes were prevented by succinate, antagonists of ionotropic glutamate receptors, and antioxidants (15,16,18).…”

Propriedades redox de canais de potássio mitocondriais ATP-sensíveis em cérebro de seu efeito neuroprotetor em excitotoxicidade

“…Esses danos ocorrem com maior freqüência em tecido cerebral devido ao maior acúmulo de MMA em decorrência da grande dependência desse tecido em metabolismo aeróbio (Hoffmann et al, 1993(Hoffmann et al, , 1994Baulny et al, 2005). Vários estudos animais in vivo e in vitro demonstram que MMA compromete a produção energética do cérebro (Marisco et al, 2003;Fleck et al, 2004;Royes et al, 2003;Brusque et al, 2002;Calabresi et al, 1998Calabresi et al, , 2001McLaughlin et al, 1998;Wajner e Coelho, 1997;Narasimhan et al, 1996;Toyoshima et al, 1995;Dutra et al, 1993;Wajner et al, 1992). MMA induz peroxidação lipídica no cérebro in vitro (Fontella et al, 2000) indicando que este ácido também pode gerar estresse oxidativo.…”