The consequences of human inborn errors in mitochondrial lipoic acid metabolism

项目总结 先天性新陈代谢错误(IEM)是导致儿童疾病和死亡的遗传性疾病；然而， 早期发现和干预使患有某些IEM的儿童能够正常发育。硫辛酸缺乏症 是一种导致代谢性酸中毒、癫痫发作和严重神经发育的新型IEM 异常现象。硫辛酸(LA)必须在哺乳动物中从头合成，是 中枢碳代谢中的基础酶。我们对乳酸代谢及其代谢的了解不足 与代谢程序的关系是治疗LA缺乏患者的主要障碍。 我们有独一无二的方法获取患者样本，通过代谢组学分析，我们发现了 与LA缺乏相关的意外代谢异常的数量；包括2- 羟基戊二酸(2-HG)，一种对细胞信号和表观遗传调节有广泛影响的代谢物。 我们打算描述人类细胞中LA代谢途径的特征，并确定有助于 2-HG的升高及其在LA缺乏中的致病作用。我们有多个LA的鼠标模型 缺陷包括一种新的敲入模型的患者突变，这种突变在胚胎上是致命的，与这些 为了研究LA缺乏对胚胎发育的影响，我们打算研究LA缺陷对胚胎发育的影响。中环 这一建议的假设是，在哺乳动物中，由于乳酸导致线粒体酶活性受损 缺乏导致代谢异常，包括2-HG的积累，这有助于 发育不正常。 如果成功，这项提议将产生一个明确的评估不同的酶在 LA途径对人类细胞中心代谢通量的影响，从而提供了代谢的详细情况 每个与LA相关的人类IEM的后果。它还将描述LA功能障碍的影响 胚胎发育过程中的体内代谢。关注患者来源的细胞和小鼠模型应该 增加提案所涵盖工作的疾病相关性。

PROJECT SUMMARY Inborn errors of metabolism (IEMs) are genetic diseases that cause illness and death in children; however, early detection and intervention permit children with some IEMs to develop normally. Lipoic acid deficiencies are a new class of IEMs that cause metabolic acidosis, seizures and severe neurodevelopmental abnormalities. Lipoic acid (LA) must be synthesized de novo in mammals and is an essential cofactor for fundamental enzymes in central carbon metabolism. Our lack of understanding LA metabolism and its relationship to metabolic programs is the primary obstacle in treating LA deficient patients. We have unique access to patient samples and through metabolomics analysis we have discovered a number of unexpected metabolic abnormalities associated with LA deficiencies; including elevation of 2- hydroxyglutarate (2-HG), a metabolite with wide reaching impacts on cell signaling and epigenetic regulation. We intend to characterize the LA metabolic pathway in human cells and identify mechanisms contributing to the elevation of 2-HG and its pathogenic role in LA deficiencies. We have multiple mouse models of LA deficiency including a novel knock-in model of a patient mutation that are embryonically lethal and with these models, we intend to investigate the impact of LA deficiencies on embryonic development. The central hypothesis of this proposal is that in mammals, impaired activity of mitochondrial enzymes due to LA deficiencies causes aberrant metabolism including accumulation of 2-HG, which contributes to abnormal development. If successful, this proposal will generate a definitive assessment of the role of distinct enzymes in the LA pathway on central metabolic fluxes in human cells, thereby providing a detailed view of the metabolic consequences of each LA-related human IEMs. It will also characterize the effects of dysfunctional LA metabolism in vivo during embryogenesis. The focus on patient-derived cells and mouse models should increase the disease relevance of the work covered in the proposal.