Mitochondrial inner membrane architecture in skeletal muscle pathophysiology

骨骼肌病理生理学中的线粒体内膜结构

基本信息

批准号：
10317296
负责人：
Bingwei Lu
金额：
$ 31.63万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-12-11 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10317296
关键词：
2019-nCoV ACE2 Administrative Supplement Affect Aging Alzheimer&apos s Disease Amyloid beta-Protein Precursor Animal Model Architecture Biogenesis Brain COVID-19 COVID-19 morbidity COVID-19 susceptibility Cells Cessation of life China Chromosome 21 Complex Congenital Heart Defects Crista ampullaris Defect Development Disease Down Syndrome Exhibits Functional disorder Gene Proteins Genes Genetic Goals Homeostasis Human Individual Infection Inner mitochondrial membrane Intellectual functioning disability Lead Lung Lung diseases Maintenance Mediating Mitochondria Mitochondrial Myopathies Molecular Muscle Muscle Cells Muscle Fibers Muscle Mitochondria Muscle hypotonia Muscular Atrophy Musculoskeletal System Myalgia Nature Neurologic Neuromuscular Diseases Obstruction Organelles Outer Mitochondrial Membrane Pathogenicity Pathologic Pathology Pathway interactions Patients Pharmaceutical Preparations Pharmacology Predisposition Presenile Alzheimer Dementia Prevention Proteins Quality Control RNA Regulation Research Respiratory System Ribosomes Role SARS coronavirus Severe Acute Respiratory Syndrome Signal Transduction Site Skeletal Muscle Structure Symptoms System Testing Therapeutic Therapeutic Agents Therapeutic Effect Tissues Viral Viral Proteins Virus base body system effective therapy induced pluripotent stem cell interest mitochondrial dysfunction mortality neuromuscular neuromuscular system novel overexpression pandemic disease parent grant patient population respiratory sarcopenia skeletal targeted agent therapeutic evaluation translocase

项目摘要

COVID-19 is an escalating pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS- CoV-2). Since its breakout in late 2019 it has spread rapidly worldwide and killed more than 600,000 people as of August 1st, 2020. There are currently no effective treatment or prevention options. Although SARS-CoV-2 causes severe respiratory disease, it also affects other organ systems, including the musculoskeletal system where myalgias, muscle loss, and muscle dysfunction are common sequelae. Down Syndrome (DS) is the most common genetic form of intellectual and developmental disabilities caused by triplication of chromosome 21. DS patients also exhibit co-occurring conditions including early-onset Alzheimer's disease (AD), congenital heart defects, respiratory and pulmonary obstructions, and muscular dysfunction. These underlying conditions make DS patients particular susceptible to COVID-19 complications. The molecular mechanisms giving rise to DS pathologies and making DS patients particularly vulnerable to COVID-19 remain elusive. Mitochondrial dysfunction is widely observed in DS and other pathological conditions affecting the neuromuscular systems such as primary mitochondrial myopathy, sarcopenia, and AD. In the parent grant, we seek to elucidate fundamental mechanisms underlying the function of mitochondrial structures in maintaining skeletal muscle integrity. We identified mitochondrial contact site and cristae organizing system (MICOS) as a critical site targeted by toxic proteins causing neuromuscular diseases. We also identified cellular quality control systems and pharmacological agents that protect against the action of such toxic proteins. In this Supplement Project, we will test the hypothesis that SARS-CoV-2 infection of muscle cells disrupts mitochondrial MICOS structure and function in normal subjects and exacerbates mitochondrial defects in DS patients. This hypothesis is based on strong premises: 1) ACE2, a key factor needed for cell entry of SARS-CoV-2, is expressed in skeletal muscle cells; 2) SARS-CoV-2 RNA is predicted to be enriched in mitochondria; 3) Certain SARS-CoV-2 encoded proteins interact with the mitochondrial TOM/TIM complex, which is known to associate with MICOS; 4) Some SARS-CoV-2 encoded proteins interact with cellular quality control pathways important for mitochondrial biogenesis and homeostasis; 5) We have observed muscle mitochondrial defects in an animal model of DS. In Aim 1, we will use human induced pluripotent stem cell (iPSC)-derived muscle cells to test the effect of SARS-CoV-2 viral proteins on mitochondrial structure/function in general and MICOS in particular in DS muscle cells. In Aim 2, we will use iPSC-derived muscle cells to test the therapeutic effect of genetic and pharmacological agents targeting mitochondrial quality control pathways. It is anticipated that by the end of the project we will have offered an explanation of the susceptibility of DS patients to SARS-CoV-2 and tested potential host-directed drugs in protecting against the pathogenic effect of SARS-CoV-2.

Covid-19是由严重急性呼吸综合征冠状病毒2（SARS- COV-2）。自2019年底突破以来，它已在全球范围内迅速传播，并杀死了60万人 2020年8月1日。目前没有有效的治疗或预防选择。虽然SARS-COV-2 引起严重的呼吸系统疾病，还会影响其他器官系统，包括肌肉骨骼系统肌痛，肌肉丧失和肌肉功能障碍是常见的后遗症。唐氏综合症（DS）是染色体的一式三份引起的智力和发育障碍的最常见遗传形式 21. DS患者还表现出同时发生的疾病，包括早期发作的阿尔茨海默氏病（AD），先天性心脏缺陷，呼吸道和肺部障碍以及肌肉功能障碍。这些基本条件使DS患者特别容易受到COVID-19并发症的影响。产生的分子机制 DS病理和使DS患者特别容易受到COVID-19的影响仍然难以捉摸。线粒体在DS和其他影响神经肌肉系统的病理状况中广泛观察到功能障碍例如原发性线粒体肌病，肌肉减少症和AD。在父母赠款中，我们寻求阐明线粒体结构在保持骨骼肌方面功能的基本机制正直。我们将线粒体接触位点和Cristae组织系统（MICOS）确定为关键部位由有毒蛋白靶向引起神经肌肉疾病。我们还确定了细胞质量控制系统和防止这种有毒蛋白质作用的药理剂。在这个补充项目中，我们将检验以下假设：SARS-COV-2肌肉细胞的感染会破坏线粒体MICOS结构 DS患者的正常受试者和加剧线粒体缺陷的功能。这个假设是基于坚固的前提：1）ACE2是SARS-COV-2细胞进入所需的关键因素，以骨骼表示肌肉细胞； 2）预计SARS-COV-2 RNA将富集在线粒体中； 3）某些SARS-COV-2 编码的蛋白质与线粒体TOM/TIM复合物相互作用，该复合物已知与MICOS相关。 4）一些SARS-COV-2编码蛋白与细胞质量控制途径相互作用线粒体生物发生和稳态； 5）我们观察到动物中的肌肉线粒体缺陷 DS的模型。在AIM 1中，我们将使用人类诱导的多能干细胞（IPSC）衍生的肌肉细胞来测试 SARS-COV-2病毒蛋白对一般的线粒体结构/功能的影响，尤其是MICOS DS肌肉细胞。在AIM 2中，我们将使用IPSC衍生的肌肉细胞来测试遗传和靶向线粒体质量控制途径的药理剂。可以预料到结束我们将提供DS患者对SARS-COV-2的敏感性并进行测试的项目潜在的宿主指导药物可防止SARS-COV-2的致病作用。