title: Neurodegeneration in methylmalonic aciduria involves inhibition of complex II and the tricarboxylic acid cycle, and synergistically acting excitotoxicity.
abstract: Methylmalonic acidurias are biochemically characterized by an accumulation of methylmalonate (MMA) and alternative metabolites. There is growing evidence for basal ganglia degeneration in these patients. The pathomechanisms involved are still unknown, a contribution of toxic organic acids, in particular MMA, has been suggested. Here we report that MMA induces neuronal damage in cultures of embryonic rat striatal cells at a concentration range encountered in affected patients. MMA-induced cell damage was reduced by ionotropic glutamate receptor antagonists, antioxidants, and succinate. These results suggest the involvement of secondary excitotoxic mechanisms in MMA-induced cell damage. MMA has been implicated in inhibition of respiratory chain complex II. However, MMA failed to inhibit complex II activity in submitochondrial particles from bovine heart. To unravel the mechanism underlying neuronal MMA toxicity, we investigated the formation of intracellular metabolites in MMA-loaded striatal neurons. There was a time-dependent intracellular increase in malonate, an inhibitor of complex II, and 2-methylcitrate, a compound with multiple inhibitory effects on the tricarboxylic acid cycle, suggesting their putative implication in MMA neurotoxicity. We propose that neuropathogenesis of methylmalonic aciduria may involve an inhibition of complex II and the tricarboxylic acid cycle by accumulating toxic organic acids, and synergistic secondary excitotoxic mechanisms.
authors.affiliation: Department of Pediatrics, Division of Metabolic and Endocrine Diseases, Im Neuenheimer Feld 150, Federal Republic of Germany. Juergen_Okun@med.uni-heidelberg.de
authors.forename: Jürgen G
authors.initials: JG
authors.lastname: Okun
authors.forename: Friederike
authors.initials: F
authors.lastname: Hörster
authors.forename: Lilla M
authors.initials: LM
authors.lastname: Farkas
authors.forename: Patrik
authors.initials: P
authors.lastname: Feyh
authors.forename: Angela
authors.initials: A
authors.lastname: Hinz
authors.forename: Sven
authors.initials: S
authors.lastname: Sauer
authors.forename: Georg F
authors.initials: GF
authors.lastname: Hoffmann
authors.forename: Klaus
authors.initials: K
authors.lastname: Unsicker
authors.forename: Ertan
authors.initials: E
authors.lastname: Mayatepek
authors.forename: Stefan
authors.initials: S
authors.lastname: Kölker
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002951:Citrates / Q000378:metabolism; D002952:Citric Acid Cycle; D003342:Corpus Striatum / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D042963:Electron Transport Complex II; D005260:Female; D008314:Malonates / Q000378:metabolism / Q000494:pharmacology; D008661:Metabolism, Inborn Errors / Q000378:metabolism / Q000503:physiopathology*; D008764:Methylmalonic Acid / Q000494:pharmacology / Q000652:urine*; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors*; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar; D013385:Succinate Dehydrogenase / Q000037:antagonists & inhibitors*
chemical_list: D002951:Citrates; D008314:Malonates; D009097:Multienzyme Complexes; C031605:2-methylcitric acid; D016202:N-Methylaspartate; D008764:Methylmalonic Acid; C030290:malonic acid; D010088:Oxidoreductases; D042963:Electron Transport Complex II; D013385:Succinate Dehydrogenase