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 Ca 2+ 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 2+ cycling and cell viability. Graphical abstract Highlights • SARS-CoV-2 perturbs human ion channel, quality control, and mitochondrial transcripts • SARS-CoV-2 proteins interact with permeability transition pore complex • SARS-CoV-2 alters VDCC activity that disrupts cardiomyocytes Ca 2+ cycling • Cyclosporin A preserves mitochondrial energetics from SARS-CoV-2 infection Cardiovascular medicine; Virology; Transcriptomics
【저자키워드】 Virology, transcriptomics, cardiovascular medicine, 【초록키워드】 COVID-19, Treatment, coronavirus disease, SARS-CoV-2, coronavirus, SARS-COV-2 infection, autophagy, cardiovascular, Endoplasmic reticulum, Disease progression, Protein, viability, Respiratory disease, transcriptomic analysis, Quality control, cell death, ORF10, cellular, cyclosporin A, NSP6, PBMCs, mitochondrial, Abstract, complex, domain, molecular basis, cellular damage, organelle, component, SARS-CoV-2 protein, ATP synthase, transcript, Mitochondrial function, Cycling, Alter, Cell, cyclosporin, ENhance, SARS-CoV-2 viral, significant changes in, lack, conducted, promote, cause, suppressed, suppress, disrupt, exacerbate, quality-control, 【제목키워드】 SARS-COV-2 infection, mitochondrial, complex, ENhance,