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

中间代谢的调节，线粒体脑肌病的新治疗方法

• 批准号: 10218518
• 负责人: Qiuying Chen
• 金额: $ 46.61万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2023-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10218518
• 关键词: Affect; Alanine; Amino Acids; Animal Model; Biochemical; Bioenergetics; Biological Markers; Blood; Carnitine; Catabolism; Cell Membrane Permeability; Cell model; Cells; Cerebrospinal Fluid; Childhood; Citric Acid Cycle; Clinical; DNA; Data; Defect; Development; Disease; Failure; Functional disorder; Generations; Genetic; Genetic Diseases; Glucocorticoid Receptor; Glucocorticoids; Glutamates; Glutamine; Glycine; Goals; Homeostasis; Human; Impairment; Inherited; Intervention; Intracellular Accumulation of Lipids; Isotopes; Knockout Mice; Knowledge; Lactic acid; Lipids; Metabolic; Metabolic Diseases; Metabolism; Mitochondria; Mitochondrial DNA; Mitochondrial Diseases; Mitochondrial Encephalomyopathies; Mus; Muscle; Muscle Cells; Muscle Mitochondria; Muscle Proteins; Muscular Atrophy; Myoblasts; Myoclonic Epilepsies; Neurologic; Nuclear; Outcome; Oxidative Phosphorylation; Oxides; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Phosphorylation; Pilot Projects; Plasma; Play; Process; Production; Proline; Proteins; Proteolysis; Publishing; Red Fiber; Regulation; Role; Sarcosine; Signal Transduction; Skeletal Muscle; Starvation; Succinate-CoA Ligases; Suggestion; Supplementation; Symptoms; System; Techniques; Testing; Therapeutic; Time; Tissues; Tricarboxylic Acids; Tyrosine; Urine; alpha ketoglutarate; analog; base; clinical effect; combinatorial; effective therapy; emerging adult; evidence base; hypothalamic-pituitary-adrenal axis; in vivo; innovation; liquid chromatography mass spectrometry; mitochondrial DNA mutation; mouse model; neuromuscular; new therapeutic target; novel; novel therapeutic intervention; organic acid; oxidation; pediatric patients; prevent; response; targeted treatment; therapeutic target; wasting

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.

项目摘要 线粒体疾病是异质性遗传性疾病，由线粒体功能受损引起。 氧化磷酸化（OXPHOS）系统，影响组织，是大量的能量 依赖性，经常表现为神经肌肉症状，伴有各种 其他临床特征。虽然由于遗传错误而产生的能量缺陷， 线粒体和核DNA通常是已知的，线粒体疾病的许多方面 发病机制尚未阐明。由于缺乏明确的 代谢目标，没有被证明有效的治疗或治愈是可用的。我们发表的研究 这表明在线粒体的小鼠模型中体内发生了显著的代谢重塑， 疾病我们发现，饥饿样反应促进肌肉蛋白质分解， 酸催化剂以支持补偿性能量产生氧化通量。在这场动荡中， 谷氨酸通过TCA循环被氧化，并允许OXPHOS非依赖性底物水平 ADP磷酸化。同时，通过β-氧化的脂质利用下调， 因此，这种适应不良的过程导致肌肉萎缩和脂质积累。重要的是， 在导致这种应用的初步研究中，我们发现， 肌阵挛癫痫和破碎红纤维（MERRF）影响的线粒体患者 脑肌病表现出类似代偿性代谢反应。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增加， 可对肌肉蛋白质和脂质平衡失调发挥作用。我们的研究结果表明， 代谢转变，倾向于优先利用氨基酸而不是脂质来提供能量 是适应不良效应的基础，有助于疾病的发病机制。在本试点研究的目标1中， 我们将提供由OXPHOS缺陷引起的代谢重新布线是常见的原则证据 线粒体疾病的动物模型和人类患者的特征。我们还将测试 假设能量底物补充可以提供有益代谢调节， 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， 在线粒体疾病小鼠模型中，通过糖皮质激素信号抑制， 用二甲基-α-酮戊二酸进行代谢补充。