tetano
Editor, Senior Moderator
iScience
. 2022 Jan 1;103722.
doi: 10.1016/j.isci.2021.103722. Online ahead of print.
SARS-CoV-2 infection enhances mitochondrial PTP complex activity to perturb cardiac energetics
Karthik Ramachandran[SUP] 1 2 [/SUP], Soumya Maity[SUP] 1 2 [/SUP], Alagar R Muthukumar[SUP] 3 [/SUP], Soundarya Kandala[SUP] 1 [/SUP], Dhanendra Tomar[SUP] 4 [/SUP], Tarek Mohamed Abd El-Aziz[SUP] 5 2 [/SUP], Cristel Allen[SUP] 1 [/SUP], Yuyang Sun[SUP] 6 [/SUP], Manigandan Venkatesan[SUP] 1 [/SUP], Travis R Madaris[SUP] 1 [/SUP], Kevin Chiem[SUP] 7 [/SUP], Rachel Truitt[SUP] 8 [/SUP], Neelanjan Vishnu[SUP] 1 [/SUP], Gregory Aune[SUP] 9 [/SUP], Allen Anderson[SUP] 1 [/SUP], Luis Martinez[SUP] 7 [/SUP], Wenli Yang[SUP] 8 [/SUP], James D Stockand[SUP] 4 [/SUP], Brij B Singh[SUP] 6 [/SUP], Subramanya Srikantan[SUP] 1 [/SUP], W Brian Reeves[SUP] 1 [/SUP], Muniswamy Madesh[SUP] 1 [/SUP]
Affiliations
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 Ca[SUP]2+[/SUP] 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 Ca[SUP]2+[/SUP] cycling and cell viability.
. 2022 Jan 1;103722.
doi: 10.1016/j.isci.2021.103722. Online ahead of print.
SARS-CoV-2 infection enhances mitochondrial PTP complex activity to perturb cardiac energetics
Karthik Ramachandran[SUP] 1 2 [/SUP], Soumya Maity[SUP] 1 2 [/SUP], Alagar R Muthukumar[SUP] 3 [/SUP], Soundarya Kandala[SUP] 1 [/SUP], Dhanendra Tomar[SUP] 4 [/SUP], Tarek Mohamed Abd El-Aziz[SUP] 5 2 [/SUP], Cristel Allen[SUP] 1 [/SUP], Yuyang Sun[SUP] 6 [/SUP], Manigandan Venkatesan[SUP] 1 [/SUP], Travis R Madaris[SUP] 1 [/SUP], Kevin Chiem[SUP] 7 [/SUP], Rachel Truitt[SUP] 8 [/SUP], Neelanjan Vishnu[SUP] 1 [/SUP], Gregory Aune[SUP] 9 [/SUP], Allen Anderson[SUP] 1 [/SUP], Luis Martinez[SUP] 7 [/SUP], Wenli Yang[SUP] 8 [/SUP], James D Stockand[SUP] 4 [/SUP], Brij B Singh[SUP] 6 [/SUP], Subramanya Srikantan[SUP] 1 [/SUP], W Brian Reeves[SUP] 1 [/SUP], Muniswamy Madesh[SUP] 1 [/SUP]
Affiliations
- PMID: 35005527
- PMCID: PMC8720045
- DOI: 10.1016/j.isci.2021.103722
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 Ca[SUP]2+[/SUP] 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 Ca[SUP]2+[/SUP] cycling and cell viability.