Mitochondrial inner membrane architecture in skeletal muscle pathophysiology

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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.