Impaired amino acid metabolism in mitochondrial diseases

线粒体疾病中氨基酸代谢受损

• 批准号: 8658872
• 负责人: Giovanni Manfredi
• 金额: $ 20.98万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8658872
• 关键词: Acids; Affect; Amino Acids; Bioenergetics; Blood; Brain; Bypass; Carbon; Cells; Cessation of life; Citric Acid Cycle; Clinical Trials; Complex; Cultured Cells; Data; Defect; Diet; Dietary Supplementation; Disease Progression; FADH2; Face; Failure; Genetic; Glutamates; Glutamine; Goals; Hereditary Disease; Homeostasis; Human; Immune system; Impairment; In Vitro; Intestines; Kidney; Liver; Mass Spectrum Analysis; Metabolic; Metabolic Pathway; Metabolism; Mitochondria; Mitochondrial Diseases; Mitochondrial Encephalomyopathies; Mus; Muscle; Mutation; Myopathy; NADH; Nervous system structure; Neurologic; Nitrogen; Nucleotide Biosynthesis; Nutritional; Organ; Outcome; Oxidation-Reduction; Oxidative Phosphorylation; Pathogenesis; Pathway interactions; Pattern; Physiological; Plasma; Play; Recruitment Activity; Respiratory Chain; Role; Skeletal Muscle; Staging; Supplementation; Symptoms; Syndrome; System; Technology; Testing; Time; Tissues; Work; base; carbohydrate metabolism; cytochrome c oxidase; improved; in vivo; lipid biosynthesis; metabolomics; mitochondrial DNA mutation; mitochondrial dysfunction; mouse model; nervous system disorder; novel strategies; pre-clinical; preclinical study; public health relevance; uptake

DESCRIPTION (provided by applicant): Mitochondrial diseases are heterogeneous genetic disorders caused by respiratory chain (RC) impairment. Attempts to treat mitochondrial diseases have been disappointing so far, mostly due to the lack of defined targets. The leading hypothesis of this application is that mitochondrial disease pathogenesis involves the blockage of crucial steps of the inter-organ amino acid metabolism. We have identified previously unrecognized defects in glutamine metabolism in cells harboring mitochondrial DNA mutations associated with human mitochondrial diseases. We found that the energetic utilization of glutamine through the glutamine-glutamate-¿-ketoglutarate pathway was impaired in these cells. We were able to rescue the metabolic defect by supplementation with compounds that bypass the enzymatic blockages. Glutamine is the most abundant and versatile circulating amino acid, mostly synthesized in skeletal muscle and released in the blood where it plays an important role as a carrier of nitrogen, carbon, and energy between organs. The various glutamine-utilization pathways in the body depend on the specialized metabolism of each tissue and play a crucial role in the inter-organs integrated metabolism that regulates metabolites homeostasis. The goal of this application is to define in vivo the altered glutamine pathways and to bypass the metabolic blockages with dietary supplementation, thus identifying new approaches to the therapy of mitochondrial diseases. To this end, we propose the following aims: 1) Metabolites imbalance in the COX10 KO mouse. We will investigate the glutamine utilization and synthesis pathways in vivo in a mouse model of RC defect caused by genetic disruption of cytochrome c oxidase (COX) assembly, resulting in a progressive mitochondriopathy. The levels of relevant metabolites will be determined in plasma and in tissues, and will be correlated with the bioenergetics, redox, acid/base and nitrogen states. The vulnerability of the affected tissues will be evaluated and correlated with disease progression. 2) Dietary supplementation in the COX10 KO mouse. In preliminary studies in vitro, metabolites that effectively bypass metabolic blocks in RC deficient cells have been identified. These metabolites will be supplemented in the diet of the COX10 KO mouse. The specialized metabolism of different tissues, the inter-organ metabolic homeostasis, and the physiological alterations in relation to disease progression will be assessed. The potential preclinical impact o this aim is that it will provide a rationale for clinical trials based on dietary supplementation, using physiological compounds.

描述（申请人提供）：线粒体疾病是由呼吸链（RC）受损引起的异质性遗传疾病。迄今为止，治疗线粒体疾病的尝试令人失望，主要是由于缺乏明确的靶点。本申请的主要假设是线粒体疾病的发病机制涉及器官间氨基酸代谢的关键步骤的阻断。我们已经确定了以前未被认识到的缺陷谷氨酰胺代谢的细胞窝藏线粒体DNA突变与人类线粒体疾病。我们发现这些细胞通过谷氨酰胺-谷氨酸-酮戊二酸途径对谷氨酰胺的能量利用受到损害。我们能够通过补充绕过酶阻塞的化合物来挽救代谢缺陷。谷氨酰胺是最丰富和最通用的循环氨基酸，主要在骨骼肌中合成并在血液中释放，在血液中作为器官之间的氮，碳和能量的载体发挥重要作用。机体内谷氨酰胺的各种利用途径依赖于各组织的专门化代谢，并在调节代谢物稳态的器官间整合代谢中起着至关重要的作用。 本申请的目的是在体内定义改变的谷氨酰胺途径，并通过膳食补充剂绕过代谢障碍，从而确定治疗线粒体疾病的新方法。为此，我们提出了以下目标：1）COX 10 KO小鼠中的代谢失衡。我们将在细胞色素c氧化酶（考克斯）组装遗传破坏引起的RC缺陷小鼠模型中研究体内谷氨酰胺的利用和合成途径，从而导致进行性线粒体病。将在血浆和组织中测定相关代谢物的水平，并将其与生物能量学、氧化还原、酸/碱和氮状态相关。将评估受影响组织的脆弱性，并将其与疾病进展相关联。 2)C 0X 10 KO小鼠中的膳食补充剂。在体外的初步研究中，已经鉴定了在RC缺陷细胞中有效绕过代谢阻断的代谢物。这些代谢物将在COX 10 KO小鼠的饮食中补充。将评估不同组织的专门代谢、器官间代谢稳态以及与疾病进展相关的生理学改变。这一目标的潜在临床前影响是，它将为使用生理化合物进行基于膳食补充剂的临床试验提供依据。