# Mitochondrial inner membrane architecture in skeletal muscle pathophysiology

> **NIH NIH R01** · STANFORD UNIVERSITY · 2021 · $316,318

## Abstract

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
...

## Key facts

- **NIH application ID:** 10317296
- **Project number:** 3R01AR074875-02S1
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Bingwei Lu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $316,318
- **Award type:** 3
- **Project period:** 2020-12-11 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10317296

## Citation

> US National Institutes of Health, RePORTER application 10317296, Mitochondrial inner membrane architecture in skeletal muscle pathophysiology (3R01AR074875-02S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10317296. Licensed CC0.

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