Impaired amino acid metabolism in mitochondrial diseases

线粒体疾病中氨基酸代谢受损

基本信息

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
项目类别：
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

项目摘要

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（由应用提供）：线粒体疾病是由呼吸链（RC）障碍引起的异质遗传疾病。到目前为止，试图治疗线粒体疾病一直令人失望，这主要是由于缺乏定义的靶标。该应用的主要假设是线粒体疾病发病机理涉及堵塞管间间氨基酸代谢的关键步骤。我们已经确定了先前未识别的缺陷，在具有与人线粒体疾病相关的线粒体DNA突变的细胞中的谷氨酰胺代谢中存在。我们发现，在这些细胞中，谷氨酰胺通过谷氨酰胺 - 酮戊二酸途径的能量利用在这些细胞中受到了损害。我们能够通过补充绕过酶促阻塞的化合物来挽救代谢缺陷。谷氨酰胺是最丰富和通用的循环氨基酸，主要是在骨骼肌中合成的，并在血液中释放，在血液中起着重要作用，作为氮，碳和器官之间的能量的重要作用。体内的各种谷氨酰胺利用途径取决于每种组织的专业代谢，并在调节代谢物稳态的孔间代谢中起着至关重要的作用。该应用的目的是在体内定义改变的谷氨酰胺途径，并绕过饮食中补充剂的代谢阻塞，从而鉴定出对线粒体疾病治疗的新方法。为此，我们提出以下目的：1）COX10 KO小鼠中的代谢产物不平衡。我们将研究由细胞色素C氧化酶（COX）组装的遗传破坏引起的RC缺陷的小鼠模型中的谷氨酰胺利用率和合成途径，从而导致了逐步的线粒体性质病。相关代谢物的水平将在血浆和组织中确定，并将与生物能，氧化还原，酸/碱和氮状态相关。受影响组织的脆弱性将与疾病进展相关。 2）在COX10 KO小鼠中补充饮食。在体外的初步研究中，已经鉴定出有效绕过RC缺乏细胞中代谢阻滞的代谢产物。这些代谢物将在Cox10 KO小鼠的饮食中补充。将评估不同组织，器官间代谢稳态的专门代谢以及与疾病进展有关的身体改变。该目标的潜在临床前影响是，它将使用物理化合物为基于饮食补充的临床试验提供理由。