A novel mechanism of mitochondrial protein turnover in Complex I deficient mitochondrial cardiomyopathy

复合物 I 缺陷型线粒体心肌病中线粒体蛋白周转的新机制

基本信息

批准号：
10708844
负责人：
Sandra Hyunjoo Lee
金额：
$ 3.82万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-30 至 2027-09-29
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10708844
关键词：
ATP Synthesis Pathway Adult Affect Antioxidants Apoptosis Bioenergetics Biological Assay Cardiac Cardiomyopathies Characteristics Child Childhood Co-Immunoprecipitations Compensation Complex Consumption Cytoprotection Data Developmental Delay Disorders Disease Electron Transport Electrons Equilibrium Flow Cytometry Functional disorder Heart Diseases Homeostasis Hydroxysteroids Hypoxia Impairment Inborn Errors of Metabolism Live Birth Longevity Malignant Neoplasms Measures Metabolic Metabolism Methods Mitochondria Mitochondrial Diseases Mitochondrial Proteins Mitochondrial complex I deficiency Modeling Morbidity - disease rate Mus Muscle Weakness Mutation Myocardial dysfunction NADH NADH dehydrogenase (ubiquinone)Nerve Degeneration Nuclear Organ Oxidation-Reduction Oxidative Stress Oxidoreductase PRDX3 peroxidase Pathologic Pathway interactions Patients Physiological Physiology Play Production Proteins Proteome Proteomics Publishing Reaction Reactive Oxygen Species Regulation Role Signaling Molecule Source Steroids Superoxides Symptoms System Testing Transfer RNA Ubiquinone Up-Regulation Work calcium uniporter cancer cell clinically relevant fatty acid metabolism fatty acid oxidation interest mitochondrial cardiomyopathies mortality mouse model new therapeutic target novel overexpression oxidative damage peroxiredoxin preservation protein degradation transcriptomics

项目摘要

PROJECT SUMMARY Mitochondria are an important source of reactive oxygen species (ROS). Once thought of inherently bad as it can cause oxidative damage, physiological ROS production is an important signaling molecule. Complex I of the mitochondria is an important source of ROS production and dysfunctional Complex I has been implicated in both mitochondrial disease and in adult-onset metabolic, neurodegenerative, cancer, and cardiac diseases. In fact, Complex I dysfunction is the most common inborn error of metabolism manifests, often resulting in pediatric mitochondrial cardiomyopathies. Our lab has been studying a mouse model of mitochondrial cardiomyopathies to discover mechanisms preserving bioenergetic homeostasis during Complex I impairment. In studying the mitochondrial calcium uniporter (MCU), an important regulator of ATP synthesis, during Complex I dysfunction, we identified a novel form of ROS-dependent protein regulation. We found that under normal circumstances, MCU transiently interacts with Complex I, and physiological ROS production in Complex I leads to MCU turnover. However, during Complex I dysfunction, the Complex I-MCU interaction is abolished, MCU lifespan increases, and this increased lifespan helps preserve mitochondrial bioenergetic homeostasis. We term this mechanism Complex I-induced protein turnover (CLIPT), and hypothesize that CLIPT is a more widespread phenomenon applicable to other mitochondrial proteins. The objective of this proposal is to determine if CLIPT is a mechanism that enables mitochondrial proteins to compensate for disruptions to cardiac mitochondrial homeostasis. In a preliminary screen, we show that a range of mitochondrial proteins may be similarly subject to CLIPT but for this proposal, I will focus on two proteins of interest: Peroxiredoxin3 (PRDX3) and Hydroxy steroid 17-beta dehydrogenase (HSD17B10). PRDX3 and HSD17B10 are interesting candidates in the setting of ROS-induced protein turnover as they play a role in an antioxidant system and in fatty acid metabolism, respectively. In Aim 1, I will demonstrate how PRDX3 and HSD17B10 is also regulated through CLIPT and in Aim 2, define the clinical relevance to upregulation of PRDX3 and HSD17B10 in the context of Complex I dysfunction. Our results may offer new targets for therapies for cardiac mitochondrial disease.

项目概要线粒体是活性氧（ROS）的重要来源。曾经认为本质上是坏的可引起氧化损伤，是生理ROS产生的重要信号分子。复合物 I 的线粒体是 ROS 产生的重要来源，功能失调的复合物 I 与线粒体疾病以及成人发病的代谢、神经退行性疾病、癌症和心脏病。在事实上，复合体 I 功能障碍是最常见的先天性代谢错误，通常会导致小儿线粒体心肌病。我们的实验室一直在研究线粒体的小鼠模型心肌病，以发现在复合物 I 损伤期间保持生物能稳态的机制。在研究线粒体钙单向转运蛋白 (MCU)（ATP 合成的重要调节因子）时，复杂的 I 功能障碍，我们发现了一种新形式的 ROS 依赖性蛋白质调节。我们发现在下正常情况下，MCU 会短暂地与 Complex I 相互作用，并产生生理性 ROS 复合体 I 导致 MCU 更新。然而，在 Complex I 功能障碍期间，Complex I-MCU 相互作用是废除后，MCU 的寿命增加，而这种增加的寿命有助于保护线粒体生物能体内平衡。我们将这种机制称为复合物 I 诱导的蛋白质周转 (CLIPT)，并假设 CLIPT 是一种更广泛的现象，适用于其他线粒体蛋白。该提案的目的是确定 CLIPT 是否是一种使线粒体蛋白能够补偿心脏线粒体稳态的破坏。在初步屏幕中，我们表明一系列线粒体蛋白可能同样受到 CLIPT 的约束，但对于这个提案，我将重点关注两个感兴趣的蛋白质：过氧化还原蛋白 3 (PRDX3) 和羟基类固醇 17-β 脱氢酶 (HSD17B10)。 PRDX3 和 HSD17B10 在 ROS 诱导的蛋白质更新中是有趣的候选者分别在抗氧化系统和脂肪酸代谢中发挥作用。在目标 1 中，我将演示如何 PRDX3 和 HSD17B10 也通过 CLIPT 进行调节，在目标 2 中，定义了与以下疾病的临床相关性：在复合物 I 功能障碍的背景下 PRDX3 和 HSD17B10 的上调。我们的结果可能会提供新的心脏线粒体疾病的治疗目标。