Department of Medicine, Center for Precision Medicine, Cardiology, Infectious Disease Divisions, University of Texas Health San Antonio, San Antonio, TX 78229, USA
Soumya Maity
Department of Medicine, Center for Precision Medicine, Cardiology, Infectious Disease Divisions, University of Texas Health San Antonio, San Antonio, TX 78229, USA
Alagar R. Muthukumar
Department of Pathology, UT Southwestern Medical Center, Dallas, TX 75390, USA
Soundarya Kandala
Department of Medicine, Center for Precision Medicine, Cardiology, Infectious Disease Divisions, University of Texas Health San Antonio, San Antonio, TX 78229, USA
Dhanendra Tomar
Department of Internal Medicine, Section on Cardiovascular Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157 USA
Tarek Mohamed Abd El-Aziz
Department of Physiology, University of Texas Health San Antonio, San Antonio, TX 78229, USA; Zoology Department, Faculty of Science, Minia University, El-Minia 61519, Egypt
Cristel Allen
Department of Medicine, Center for Precision Medicine, Cardiology, Infectious Disease Divisions, University of Texas Health San Antonio, San Antonio, TX 78229, USA
Yuyang Sun
Department of Periodontics, University of Texas Health San Antonio, San Antonio, TX 78229, USA
Manigandan Venkatesan
Department of Medicine, Center for Precision Medicine, Cardiology, Infectious Disease Divisions, University of Texas Health San Antonio, San Antonio, TX 78229, USA
Travis R. Madaris
Department of Medicine, Center for Precision Medicine, Cardiology, Infectious Disease Divisions, University of Texas Health San Antonio, San Antonio, TX 78229, USA
Kevin Chiem
Texas Biomedical Research Institute, San Antonio, TX 78227, USA
Rachel Truitt
Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Neelanjan Vishnu
Department of Medicine, Center for Precision Medicine, Cardiology, Infectious Disease Divisions, University of Texas Health San Antonio, San Antonio, TX 78229, USA
Gregory Aune
Department of Pediatrics, Greehey Children's Cancer Research Institute, Division of Hematology-Oncology, University of Texas Health San Antonio, San Antonio, TX 78229, USA
Allen Anderson
Department of Medicine, Center for Precision Medicine, Cardiology, Infectious Disease Divisions, University of Texas Health San Antonio, San Antonio, TX 78229, USA
Luis Martinez
Texas Biomedical Research Institute, San Antonio, TX 78227, USA
Wenli Yang
Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
James D. Stockand
Department of Internal Medicine, Section on Cardiovascular Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157 USA
Brij B. Singh
Department of Periodontics, University of Texas Health San Antonio, San Antonio, TX 78229, USA
Subramanya Srikantan
Department of Medicine, Center for Precision Medicine, Cardiology, Infectious Disease Divisions, University of Texas Health San Antonio, San Antonio, TX 78229, USA; Corresponding author
W. Brian Reeves
Department of Medicine, Center for Precision Medicine, Cardiology, Infectious Disease Divisions, University of Texas Health San Antonio, San Antonio, TX 78229, USA; Corresponding author
Muniswamy Madesh
Department of Medicine, Center for Precision Medicine, Cardiology, Infectious Disease Divisions, University of Texas Health San Antonio, San Antonio, TX 78229, USA; Corresponding author
Summary: SARS-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.