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.

新冠肺炎是由严重急性呼吸综合征冠状病毒2(SARS-1)引起的一种不断升级的流行病。 CoV-2)。自2019年底爆发以来，它在全球迅速传播，并在 2020年8月1日。目前还没有有效的治疗或预防选择。虽然SARS-CoV-2 会导致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、肌肉萎缩和肌肉功能障碍是常见的后遗症。唐氏综合症(DS)是 最常见的由染色体三倍体引起的智力和发育障碍的遗传形式 21.DS患者还表现出包括早发性阿尔茨海默病(AD)、先天性 心脏缺陷，呼吸和肺阻塞，以及肌肉功能障碍。这些潜在的条件 使DS患者特别容易发生新冠肺炎并发症。引起人类免疫缺陷的分子机制 DS的病理机制和使DS患者对新冠肺炎特别脆弱的问题仍然难以捉摸。线粒体 在DS和其他影响神经肌肉系统的病理情况下，功能障碍被广泛观察到 如原发性线粒体肌病、骨质疏松症和AD。在家长赠款中，我们试图澄清 线粒体结构维持骨骼肌功能的基本机制 正直。我们确定线粒体接触部位和脊组织系统(MICOS)是一个关键部位 以引起神经肌肉疾病的有毒蛋白质为靶标。我们还确定了细胞质量控制系统 以及防止这种有毒蛋白质作用的药理制剂。在本增刊项目中， 我们将验证肌肉细胞感染SARS-CoV-2破坏线粒体MICOS结构的假设 和功能正常受试者，并加剧线粒体缺陷的DS患者。这一假设是 基于很强的前提：1)SARS-CoV-2进入细胞所需的关键因子ACE2在骨骼中表达 肌肉细胞；2)SARS-CoV-2RNA被预测在线粒体中富含；3)某些SARS-CoV-2 编码蛋白与线粒体TOM/TIM复合体相互作用，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，这些途径对 线粒体的生物发生和动态平衡；5)我们观察到一种动物的肌肉线粒体缺陷 DS的模型。在目标1中，我们将使用人诱导多能干细胞(IPSC)来源的肌肉细胞来测试 SARS-CoV-2病毒蛋白对线粒体结构/功能及MICOS的影响 DS肌细胞。在目标2中，我们将使用IPSC来源的肌肉细胞来测试遗传和 以线粒体质量控制通路为靶点的药物。预计到年底， 我们将对DS患者对SARS-CoV-2的易感性进行解释并进行测试 抗SARS-CoV-2致病作用的潜在宿主导向药物。