Neurodegeneration in methylmalonic aciduria involves inhibition of complex II and the tricarboxylic acid cycle, and synergistically acting excitotoxicity
Neurodegeneration in methylmalonic aciduria involves inhibition of complex II and the tricarboxylic acid cycle, and synergistically acting excitotoxicity
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DOI：
10.1074/jbc.m200997200
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发表时间：
2002-04-26
影响因子：
4.8
通讯作者：
Kölker, S
中科院分区：
文献类型：
--
作者：
Okun, JG;Hörster, F;Kölker, S
甲基丙二酸尿症的生化特征是甲基丙二酸（MMA）和替代代谢物的蓄积。越来越多的证据表明这些患者存在基底神经节变性。所涉及的病理机制仍然是未知的，有毒的有机酸，特别是MMA的贡献，已被建议。在这里，我们报告说，MMA诱导胚胎大鼠纹状体细胞在受影响的患者遇到的浓度范围内的文化神经元损伤。离子型谷氨酸受体拮抗剂、抗氧化剂和琥珀酸盐可降低MMA诱导的细胞损伤。这些结果表明，在MMA诱导的细胞损伤的二级兴奋性毒性机制的参与。MMA与呼吸链复合物II的抑制有关。然而，MMA未能抑制复合物II活性亚线粒体颗粒从牛心脏。为了阐明神经元MMA毒性的机制，我们研究了MMA负载纹状体神经元细胞内代谢产物的形成。丙二酸盐（复合物II的抑制剂）和2-甲基柠檬酸盐（一种对三羧酸循环具有多重抑制作用的化合物）的细胞内浓度呈时间依赖性增加，表明其在MMA神经毒性中的推定意义。我们建议，甲基丙二酸尿症的神经发病机制可能涉及抑制复合物II和三羧酸循环，通过积累有毒的有机酸，协同继发兴奋性毒性机制。
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.