Sauer Sven W, Okun Jürgen G, Schwab Marina A, Crnic Linda R, Hoffmann Georg F, Goodman Stephen I, Koeller David M, Kölker Stefan
Department of General Pediatrics, Division of Inborn Metabolic Diseases, University Children's Hospital of Heidelberg, Im Neuenheimer Feld 150, D-69120 Heidelberg, Germany.
J Biol Chem. 2005 Jun 10;280(23):21830-6. doi: 10.1074/jbc.M502845200. Epub 2005 Apr 19.
Inherited deficiency of glutaryl-CoA dehydrogenase results in an accumulation of glutaryl-CoA, glutaric, and 3-hydroxyglutaric acids. If untreated, most patients suffer an acute encephalopathic crisis and, subsequently, acute striatal damage being precipitated by febrile infectious diseases during a vulnerable period of brain development (age 3 and 36 months). It has been suggested before that some of these organic acids may induce excitotoxic cell damage, however, the relevance of bioenergetic impairment is not yet understood. The major aim of our study was to investigate respiratory chain, tricarboxylic acid cycle, and fatty acid oxidation in this disease using purified single enzymes and tissue homogenates from Gcdh-deficient and wild-type mice. In purified enzymes, glutaryl-CoA but not glutaric or 3-hydroxyglutaric induced an uncompetitive inhibition of alpha-ketoglutarate dehydrogenase complex activity. Notably, reduced activity of alpha-ketoglutarate dehydrogenase activity has recently been demonstrated in other neurodegenerative diseases, such as Alzheimer, Parkinson, and Huntington diseases. In contrast to alpha-ketoglutarate dehydrogenase complex, no direct inhibition of glutaryl-CoA, glutaric acid, and 3-hydroxyglutaric acid was found in other enzymes tested. In Gcdh-deficient mice, respiratory chain and tricarboxylic acid activities remained widely unaffected, virtually excluding regulatory changes in these enzymes. However, hepatic activity of very long-chain acyl-CoA dehydrogenase was decreased and concentrations of long-chain acylcarnitines increased in the bile of these mice, which suggested disturbed oxidation of long-chain fatty acids. In conclusion, our results demonstrate that bioenergetic impairment may play an important role in the pathomechanisms underlying neurodegenerative changes in glutaryl-CoA dehydrogenase deficiency.
戊二酰辅酶A脱氢酶的遗传性缺乏会导致戊二酰辅酶A、戊二酸和3-羟基戊二酸的积累。如果不进行治疗，大多数患者会经历急性脑病危机，随后在脑发育的脆弱期（3至36个月）因发热性传染病而引发急性纹状体损伤。之前有人提出，这些有机酸中的一些可能会诱导兴奋性毒性细胞损伤，然而，生物能量损害的相关性尚未明确。我们研究的主要目的是使用来自戊二酰辅酶A脱氢酶缺乏型和野生型小鼠的纯化单一酶和组织匀浆，研究这种疾病中的呼吸链、三羧酸循环和脂肪酸氧化。在纯化的酶中，戊二酰辅酶A而非戊二酸或3-羟基戊二酸对α-酮戊二酸脱氢酶复合体活性产生非竞争性抑制。值得注意的是，最近在其他神经退行性疾病如阿尔茨海默病、帕金森病和亨廷顿病中也发现了α-酮戊二酸脱氢酶活性降低。与α-酮戊二酸脱氢酶复合体不同，在测试的其他酶中未发现戊二酰辅酶A、戊二酸和3-羟基戊二酸有直接抑制作用。在戊二酰辅酶A脱氢酶缺乏型小鼠中，呼吸链和三羧酸活性基本未受影响，实际上排除了这些酶的调节变化。然而，这些小鼠肝脏中极长链酰基辅酶A脱氢酶的活性降低，胆汁中长链酰基肉碱的浓度升高，这表明长链脂肪酸氧化受到干扰。总之，我们的结果表明，生物能量损害可能在戊二酰辅酶A脱氢酶缺乏导致的神经退行性变化的发病机制中起重要作用。
