Modulation of intermediate metabolism, a new therapeutic approach for mitochondrial encephalomyopathies

项目摘要 线粒体疾病是由线粒体功能受损引起的异质性遗传病。 氧化磷酸化(OXPHOS)系统，影响能量旺盛的组织 依赖性的，经常表现为神经肌肉症状，伴随着各种 其他临床特征。尽管由遗传错误引起的能量缺陷 线粒体和核DNA通常是已知的，线粒体疾病的许多方面 发病机制尚不清楚。因此，由于缺乏明确的 新陈代谢的目标，没有被证明有效的治疗或治愈方法。我们已发表的研究 表明在体内线粒体模型中发生了戏剧性的代谢重塑 疾病。我们发现类似饥饿的反应促进了肌肉蛋白质的分解和氨基酸的合成 酸的分解代谢支持一种补偿性的产生能量的氧化通量。在这种变化中， 谷氨酸通过TCA循环被氧化，并允许OXPHOS不依赖底物水平 ADP磷酸化。同时，通过氧化的脂质利用被下调，并 因此，这种不适应的过程会导致肌肉萎缩和脂肪堆积。重要的是 在导致这一应用的初步研究中，我们发现来自 肌阵挛癫痫和粗糙红纤维(MERRF)患者的线粒体 脑肌病表现出类似的代偿性代谢反应。我们还发现， 下丘脑-垂体-肾上腺轴改变导致糖皮质激素水平升高， 能起到肌肉蛋白质和脂肪代谢紊乱的作用。我们的发现表明这一点 代谢转向优先利用氨基酸而不是脂类以达到能量目的 导致适应不良，导致疾病的发病机制。在这项初步研究的目标1中， 我们将提供由OXPHOS缺陷引起的新陈代谢重新连接的原则证据 线粒体疾病的动物模型和人类患者的特征。我们还将测试 补充能量底物可以提供有益的代谢调节的假说 患者来源的肌肉细胞。此外，在目标2中，我们将测试一种创新的代谢疗法 在糖皮质激素信号抑制加或不加糖皮质激素信号抑制的线粒体疾病小鼠模型中 α-酮戊二酸二甲酯的代谢补充。

Project Summary Mitochondrial diseases are heterogeneous genetic disorders caused by the impairment of the oxidative phosphorylation (OXPHOS) system, affecting tissues that are heavily energy dependent, and often manifesting with neuromuscular symptoms accompanied by a variety of additional clinical features. Although the energetic defects arising from genetic errors in mitochondrial and nuclear DNA are often known, many aspects of mitochondrial disease pathogenesis are yet to be elucidated. As a consequence, because of the lack of defined metabolic targets, no proven effective treatments or cures are available. Our published studies indicate that a dramatic metabolic remodeling occurs in vivo in a mouse model of mitochondrial disease. We found that a starvation-like response promotes muscle protein breakdown and amino acid catabolism to support a compensatory energy-generating oxidative flux. In this flux, glutamate is oxidized through the TCA cycle and allows for OXPHOS-independent substrate-level ADP phosphorylation. At the same time, lipid utilization through -oxidation is downregulated and therefore this maladaptive process results in muscle wasting and lipid accumulation. Importantly, in preliminary studies leading to this application, we have discovered that skeletal muscle from mitochondrial patients affected by Myoclonus Epilepsy and Ragged Red Fibers (MERRF) encephalomyopathy show similar compensatory metabolic responses. We also find that the hypothalamic–pituitary–adrenal axis is altered leading to increased glucocorticoid levels, which can play a role in muscle protein and lipid dyshomeostasis. Our findings suggest that this metabolic shift towards preferred utilization of amino acids over lipids for energetic purposes underlies maladaptive effects, contributing to disease pathogenesis. In aim 1 of this pilot study, we will provide proof of principle that metabolic rewiring caused by OXPHOS defects are common features in animal models and human patients with mitochondrial diseases. We will also test the hypothesis that energy substrate supplementation can provide beneficial metabolic modulation in patient-derived muscle cells. Furthermore, in aim 2, we will test an innovative metabolic therapy in a mouse model of mitochondrial disease by glucocorticoid signal inhibition with or without metabolic supplementation with dimethyl-alpha ketoglutarate.