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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要线粒体疾病是由线粒体损伤引起的异质性遗传性疾病。氧化磷酸化（OXPHOS）系统，影响能量消耗严重的组织依赖性，常表现为神经肌肉症状，并伴有各种症状额外的临床特征虽然是由遗传错误引起的。线粒体和核 DNA 众所周知，线粒体疾病的许多方面由于缺乏明确的发病机制，目前尚未阐明。代谢目标，目前尚无经过证实的有效治疗方法或治愈方法。表明在小鼠线粒体模型中体内发生了显着的代谢重塑我们发现类似饥饿的反应会促进肌肉蛋白质分解和氨基酸。酸分解代谢以支持补偿性能量产生氧化通量在该通量中，谷氨酸通过 TCA 循环被氧化，并实现不依赖于 OXPHOS 的底物水平同时，ADP 磷酸化通过  氧化作用下调并发挥作用。因此，这种适应不良的过程会导致肌肉萎缩和脂质积累。在导致该应用的初步研究中，我们发现骨骼肌来自患有肌阵挛癫痫和锯齿状红纤维 (MERRF) 的线粒体患者我们还发现脑肌病表现出类似的代偿性代谢反应。下丘脑-垂体-肾上腺轴导致糖皮质激素水平升高，从而我们的研究结果表明，它可以在肌肉蛋白质和脂质稳态失衡中发挥作用。为了能量目的，代谢转变为优先利用氨基酸而不是脂质是适应不良效应的基础，导致疾病发病机制在本试点研究的目标 1 中，我们将提供原理证明，证明 OXPHOS 缺陷引起的代谢重新布线是常见的我们还将测试动物模型和患有线粒体疾病的人类患者的特征。假设补充能量底物可以提供有益的代谢调节此外，在目标 2 中，我们将测试一种创新的代谢疗法。在通过糖皮质激素信号抑制（有或没有）的线粒体疾病小鼠模型中代谢补充二甲基-α酮戊二酸。