SARS-CoV-2 infection enhances mitochondrial PTP complex activity to perturb cardiac energetics

Karthik Ramachandran,Alagar R Muthukumar,Tarek Mohamed Abd El-Aziz,Wenli Yang,Subramanya Srikantan,Dhanendra Tomar,Neelanjan Vishnu,Yuyang Sun,Soumya Maity,James D Stockand,Rachel Truitt,Cristel Allen,Kevin Chiem,Muniswamy Madesh,Soundarya Kandala,Manigandan Venkatesan,Travis R Madaris,W Brian Reeves,Brij B Singh,Gregory J Aune ,Allen A Anderson ,Luis Martinez

doi:10.1016/j.isci.2021.103722

Abstract

SummarySARS-CoV-2 is a newly identified coronavirus that causes the respiratory disease called coronavirus disease 2019 (COVID-19). With an urgent need for therapeutics, we lack a full understanding of the molecular basis of SARS-CoV-2-induced cellular damage and disease progression. Here, we conducted transcriptomic analysis of human PBMCs, identified significant changes in mitochondrial, ion channel, and protein quality-control gene products. SARS-CoV-2 proteins selectively target cellular organelle compartments, including the endoplasmic reticulum and mitochondria. M-protein, NSP6, ORF3A, ORF9C, and ORF10 bind to mitochondrial PTP complex components cyclophilin D, SPG-7, ANT, ATP synthase, and a previously undescribed CCDC58 (coiled-coil domain containing protein 58). Knockdown of CCDC58 or mPTP blocker cyclosporin A pretreatment enhances mitochondrial Ca2+ retention capacity and bioenergetics. SARS-CoV-2 infection exacerbates cardiomyocyte autophagy and promotes cell death that was suppressed by cyclosporin A treatment. Our findings reveal that SARS-CoV-2 viral proteins suppress cardiomyocyte mitochondrial function that disrupts cardiomyocyte Ca2+ cycling and cell viability.

Highlights

Several million people worldwide have been infected with coronavirus-SARS-CoV-2, the causative agent of the coronavirus disease 2019 (COVID-19) pandemic, our understanding of the fundamental mechanisms underlying the clinical manifestation of COVID-19 is still emerging
With an urgent need for therapeutics, we lack a full understanding of the molecular basis of SARS-CoV-2-induced cellular damage and disease progression
SARS-CoV-2 infection exacerbates cardiomyocyte autophagy and promotes cell death that was suppressed by cyclosporin A treatment

Summary

Introduction

Several million people worldwide have been infected with coronavirus-SARS-CoV-2, the causative agent of the coronavirus disease 2019 (COVID-19) pandemic, our understanding of the fundamental mechanisms underlying the clinical manifestation of COVID-19 is still emerging. The SARS-CoV-2 entry receptor, ACE2 is highly expressed in several cell types, including myocardial cells, kidney proximal tubule cells, type II alveolar cells, and lymphocytes located in oral mucosa and other tissues. Beyond this canonical entry pathway, the mechanisms of cellular damage and tissue injury are poorly understood but are of paramount importance. A deeper understanding of the mechanisms underlying myocardial injury is needed to develop a therapeutic strategy for such patients with co-morbidities

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