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, Wenli Yang, James D. Stockand, Brij B. Singh, Subramanya SrikantanW. Brian Reeves, Muniswamy Madesh

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article number103722
JournaliScience
Volume25
Issue number1
DOIs
StatePublished - Jan 21 2022
Externally publishedYes

Keywords

  • Cardiovascular medicine
  • Transcriptomics
  • Virology

ASJC Scopus subject areas

  • General

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