TY - JOUR
T1 - SARS-CoV-2 infection enhances mitochondrial PTP complex activity to perturb cardiac energetics
AU - Ramachandran, Karthik
AU - Maity, Soumya
AU - Muthukumar, Alagar R.
AU - Kandala, Soundarya
AU - Tomar, Dhanendra
AU - Abd El-Aziz, Tarek Mohamed
AU - Allen, Cristel
AU - Sun, Yuyang
AU - Venkatesan, Manigandan
AU - Madaris, Travis R.
AU - Chiem, Kevin
AU - Truitt, Rachel
AU - Vishnu, Neelanjan
AU - Aune, Gregory
AU - Anderson, Allen
AU - Martinez, Luis
AU - Yang, Wenli
AU - Stockand, James D.
AU - Singh, Brij B.
AU - Srikantan, Subramanya
AU - Reeves, W. Brian
AU - Madesh, Muniswamy
N1 - Funding Information:
This research was funded by the National Institutes of Health ( R01GM109882 , R01HL086699 , R01HL142673 , R01GM135760 , and 1S10RR027327 ) to M.M. This work was partly supported by DOD /DHP- CDMRP PR181598P-1 and San Antonio Partnership for Precision Therapeutics ( SAPPT ) to M.M. and the COVID-19 research was partly supported by the UTHSA COVID-19 pilot grant to M.M.
Funding Information:
This research was funded by the National Institutes of Health (R01GM109882, R01HL086699, R01HL142673, R01GM135760, and 1S10RR027327) to M.M. This work was partly supported by DOD/DHP-CDMRP PR181598P-1 and San Antonio Partnership for Precision Therapeutics (SAPPT) to M.M. and the COVID-19 research was partly supported by the UTHSA COVID-19 pilot grant to M.M. K.R. S.M. S.K. D.T. C.A. M.V. T.R.M. G.A. N.V. S.S. and M.M. performed and analyzed experiments involving RNA-seq analysis and biochemical, cell biological, and mitochondrial parameters. T.A. Y.S. J.D.S. and B.B.S. performed electrophysiology and analysis. A.R.M. collected PBMCs from human subjects and measured clinical parameters. K.C. and L.M. conducted SARS-CoV-2 infection, RNA isolation from human PBMCs, and cell death assay. R.T. and W.Y. generated iPSC-derived human cardiomyocytes. A.A. L.M. J.D.S. B.B.S. S.S. W.B.R. and M.M. analyzed and interpreted experimental data. B.B.S. S.S. W.B.R. and M.M. conceived, designed, and wrote the manuscript. All authors commented on the manuscript. All authors declare no competing interests.
Publisher Copyright:
© 2022 The Authors
PY - 2022/1/21
Y1 - 2022/1/21
N2 - 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.
AB - 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.
KW - Cardiovascular medicine
KW - Transcriptomics
KW - Virology
UR - http://www.scopus.com/inward/record.url?scp=85123514357&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85123514357&partnerID=8YFLogxK
U2 - 10.1016/j.isci.2021.103722
DO - 10.1016/j.isci.2021.103722
M3 - Article
C2 - 35005527
AN - SCOPUS:85123514357
SN - 2589-0042
VL - 25
JO - iScience
JF - iScience
IS - 1
M1 - 103722
ER -