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

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

doi:10.1016/j.isci.2021.103722

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

iScience. 2022 Jan 1;25(1):103722. doi: 10.1016/j.isci.2021.103722. eCollection 2022 Jan 21.

Authors

Karthik Ramachandran¹, Soumya Maity¹, Alagar R Muthukumar², Soundarya Kandala¹, Dhanendra Tomar³, Tarek Mohamed Abd El-Aziz^{4

5}, Cristel Allen¹, Yuyang Sun⁶, Manigandan Venkatesan¹, Travis R Madaris¹, Kevin Chiem⁷, Rachel Truitt⁸, Neelanjan Vishnu¹, Gregory Aune⁹, Allen Anderson¹, Luis Martinez-Sobrido⁷, Wenli Yang⁸, James D Stockand³, Brij B Singh⁶, Subramanya Srikantan¹, W Brian Reeves¹, Muniswamy Madesh¹

Affiliations

¹ Department of Medicine, Center for Precision Medicine, Cardiology, Infectious Disease Divisions, University of Texas Health San Antonio, San Antonio, TX 78229, USA.
² Department of Pathology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
³ Department of Internal Medicine, Section on Cardiovascular Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157 USA.
⁴ Department of Physiology, University of Texas Health San Antonio, San Antonio, TX 78229, USA.
⁵ Zoology Department, Faculty of Science, Minia University, El-Minia 61519, Egypt.
⁶ Department of Periodontics, University of Texas Health San Antonio, San Antonio, TX 78229, USA.
⁷ Texas Biomedical Research Institute, San Antonio, TX 78227, USA.
⁸ Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁹ Department of Pediatrics, Greehey Children's Cancer Research Institute, Division of Hematology-Oncology, University of Texas Health San Antonio, San Antonio, TX 78229, USA.

Abstract

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.

Keywords: Cardiovascular medicine; Transcriptomics; Virology.

Abstract

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