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

• 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
• 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' 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

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- 冠状病毒-2）。自 2019 年底爆发以来，它已在全球范围内迅速传播，并导致超过 60 万人死亡。 2020 年 8 月 1 日起。目前尚无有效的治疗或预防方案。尽管 SARS-CoV-2 导致严重的呼吸道疾病，它还会影响其他器官系统，包括肌肉骨骼系统 肌痛、肌肉损失和肌肉功能障碍是常见的后遗症。唐氏综合症 (DS) 是 由染色体三倍体引起的智力和发育障碍的最常见遗传形式 21. DS 患者还表现出并发病症，包括早发性阿尔茨海默病 (AD)、先天性 心脏缺陷、呼吸和肺部阻塞以及肌肉功能障碍。这些基本条件 使 DS 患者特别容易出现 COVID-19 并发症。产生的分子机制 DS 病理以及使 DS 患者特别容易感染 COVID-19 的情况仍然难以捉摸。线粒体 功能障碍在 DS 和影响神经肌肉系统的其他病理状况中广泛观察到 如原发性线粒体肌病、肌少症和 AD。在家长补助金中，我们试图阐明 线粒体结构维持骨骼肌功能的基本机制 正直。我们将线粒体接触位点和嵴组织系统 (MICOS) 确定为关键位点 受到引起神经肌肉疾病的有毒蛋白质的靶向。我们还确定了细胞质量控制系统 以及防止此类有毒蛋白质作用的药剂。在这个补充项目中， 我们将测试肌肉细胞的 SARS-CoV-2 感染破坏线粒体 MICOS 结构的假设 和正常受试者的功能，并加剧 DS 患者的线粒体缺陷。这个假设是 基于强有力的前提：1) ACE2 是 SARS-CoV-2 进入细胞所需的关键因子，在骨骼中表达 肌肉细胞； 2）预计SARS-CoV-2 RNA在线粒体中富集； 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，已知该复合物与 MICOS 相关； 4) 一些 SARS-CoV-2 编码的蛋白质与细胞质量控制途径相互作用，对于 线粒体生物发生和稳态； 5）我们观察到动物的肌肉线粒体缺陷 DS 模型。在目标 1 中，我们将使用人类诱导多能干细胞 (iPSC) 衍生的肌肉细胞来测试 SARS-CoV-2 病毒蛋白对线粒体结构/功能的总体影响，特别是对 MICOS 的影响 DS 肌细胞。在目标 2 中，我们将使用 iPSC 衍生的肌肉细胞来测试遗传和治疗的治疗效果。 针对线粒体质量控制途径的药物制剂。预计到年底 项目中，我们将解释 DS 患者对 SARS-CoV-2 的易感性并进行测试 潜在的针对宿主的药物可预防 SARS-CoV-2 的致病作用。