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Metabolic Impact and Mechanism of Enhanced Mitochondrial Calcium Uptake in Mitochondrial Cardiomyopathies

线粒体钙摄取增强对线粒体心肌病的代谢影响和机制

基本信息

批准号：
10753651
负责人：
Dipayan Chaudhuri
金额：
$ 60.42万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-05-15 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10753651
关键词：
ATP Synthesis Pathway Address Adenine Affect Animals Antioxidants Binding Bioenergetics Biological Assay Biology Calcium Calcium Signaling Carbon Cardiac Cardiomyopathies Child Childhood Complex Cytoprotection Dependovirus Dinucleoside Phosphates Disease Drosophila genus Enzymes Equilibrium Functional disorder Heart Heart Injuries Heart failure Homeostasis Human Impairment Inborn Errors of Metabolism Infant Link Mediating Metabolic Metabolism Mitochondria Mitochondrial DNA Mitochondrial Matrix Modeling Mus Mutation N-terminal NADH NADH dehydrogenase (ubiquinone)NADP Niacinamide Organ Outcome Oxidation-Reduction Oxidative Phosphorylation Pathologic Pathologic Processes Pathology Pathway interactions Physiological Physiology Prevalence Production Prognosis Proteins Reactive Oxygen Species Regulation Regulatory Pathway Signal Transduction Testing Therapeutic Up-Regulation Work calcium uniporter disease-causing mutation functional improvement heart function heart metabolism heart preservation improved mitochondrial cardiomyopathies mitochondrial metabolism mortality mouse model neonatal mice novel novel therapeutics preservation prevent protein degradation transcription factor transgene expression uptake virtual

项目摘要

PROJECT SUMMARY Diseases that arise from mutations in components of mitochondrial oxidative phosphorylation can be devastating, as mitochondria are crucial for energy synthesis. These diseases occur predominantly in infants and children, with a prevalence of 1 in 5000. Though virtually any organ can be affected, the heart is frequently involved, because cardiac function has such high energy requirements. These mitochondrial cardiomyopathies have a particularly grim prognosis, with mortality rates increased nearly three-fold compared to children without cardiac involvement, and no specific therapies available. In linking cardiac function to mitochondrial metabolism, calcium signaling may be central to the pathological process. Calcium influx into the mitochondria can potently stimulate ATP synthesis. In the initial period of this application, we identified a regulatory mechanism by which dysfunction within Complex I of the electron transport chain causes a compensatory increase in activity of the mitochondrial calcium uniporter channel, preserving ATP synthesis. During normal physiology, Complex I promotes uniporter degradation via an interaction with the uniporter, a mechanism we term Complex I-induced protein turnover (CLIPT). During Complex I dysfunction, interaction with the uniporter is inhibited, preventing degradation and leading to a build-up in functional channels. This mechanism is widespread and was seen in fruit flies, mice, and humans. Moreover, while inhibiting the uniporter led to early demise in Complex I-deficient animals, enhancing uniporter stability rescued survival and function. In this project period, we propose the following three aims to further study this pathway and determine whether it can be exploited for potential therapeutic benefit. We focus on mitochondrial one-carbon (1C) metabolism, a producer of mitochondrial antioxidant species (NAPDH), because this pathway is substantially upregulated in mitochondrial cardiomyopathies. In the first aim, we will examine if adenine dinucleotides (NAD+/NADP+) regulate the uniporter, and if calcium regulates critical 1C metabolism enzymes. In the second aim, we will establish whether uniporter activity in mitochondrial cardiomyopathies extends beyond ATP synthesis to NADPH biology, affecting redox balance and one-carbon metabolism. In the third aim, we will test whether manipulation of the portion of the uniporter that interacts with Complex I, the uniporter N-terminal domain (NTD), can be exploited in mouse models as a potential therapy for mitochondrial cardiomyopathies.

项目总结