Inhibition of brain energy metabolism by the α-keto acids accumulating in maple syrup urine disease
Inhibition of brain energy metabolism by the α-keto acids accumulating in maple syrup urine disease
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DOI：
10.1016/j.bbadis.2003.09.010
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发表时间：
2003-11-20
影响因子：
6.2
通讯作者：
Wajner, M
中科院分区：
文献类型：
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作者：
Sgaravatti, AM;Rosa, RB;Wajner, M
神经功能障碍是枫糖尿病(MSUD)患者的常见症状。然而，这种疾病中脑损伤的神经病理机制却鲜为人知。在本研究中，我们研究了在MSUD中积累的支链α-酮酸(BCKA)对大鼠大脑皮层能量代谢某些参数的影响。[(CO2)-C-14][C-14]醋酸酯的产生、葡萄糖的摄取和葡萄糖的释放是通过将30天大鼠的皮质棱镜置于pH为7.4的Krebs-Ringer重碳酸盐缓冲液中进行的，在没有(对照)或存在1-5 mM的α-酮基异己酸(KIC)、α-酮-β-甲基戊酸(KNW)或α-酮异戊酸(KIV)的情况下，评估了[(CO2)-C-14]的产生、葡萄糖摄取和葡萄糖释放。所有酮酸显著减少(CO2)-C-14的产生约40%，相比之下，乳酸释放和葡萄糖利用显著增加约42%的代谢物在皮质棱镜。此外，呼吸链复合体I-III的活性被显著抑制60%，而电子传递链的其他活性，即复合体II、II-III、III和IV以及琥珀酸脱氢酶不受酮酸的影响。结果表明，MSUD中积累的主要代谢物通过阻断呼吸链影响大脑能量代谢。我们推测，这些发现可能与理解MSUD患者神经功能障碍的病理生理学有关。(C)2003爱思唯尔B.V.保留所有权利。
Neurological dysfunction is a common finding in patients with maple syrup urine disease (MSUD). However, the mechanisms underlying the neuropathology of brain damage in this disorder are poorly known. In the present study, we investigated the effect of the in vitro effect of the branched chain alpha-keto acids (BCKA) accumulating in MSUD on some parameters of energy metabolism in cerebral cortex of rats. [(CO2)-C-14] production from [C-14] acetate, glucose uptake and lactate release from glucose were evaluated by incubating cortical prisms from 30-day-old rats in Krebs-Ringer bicarbonate buffer, pH 7.4, in the absence (controls) or presence of 1-5 mM of alpha-ketoisocaproic acid (KIC), alpha-keto-beta-methylvaleric acid (KNW) or alpha-ketoisovaleric acid (KIV). All keto acids significantly reduced (CO2)-C-14 production by around 40%, in contrast to lactate release and glucose utilization, which were significantly increased by the metabolites by around 42% in cortical prisms. Furthermore, the activity of the respiratory chain complex I-III was significantly inhibited by 60%, whereas the other activities of the electron transport chain, namely complexes II, II-III, III and IV, as well as succinate dehydrogenase were not affected by the keto acids. The results indicate that the major metabolites accumulating in MSUD compromise brain energy metabolism by blocking the respiratory chain. We presume that these findings may be of relevance to the understanding of the pathophysiology of the neurological dysfunction of MSUD patients. (C) 2003 Elsevier B.V. All rights reserved.