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

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 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.

SARS-CoV-2 infection and replication kinetics in different human cell types: The role of autophagy, cellular metabolism and ACE2 expression

“…A previous study reported that mitochondrial metabolism was disturbed by SARS-CoV-2 infection, and enhanced mitochondrial permeability transition pore (PTP) activity has been observed upon the virus infection in human PBMCs [38] . In another report, a transcriptome databank of cell and clinical samples revealed that cellular respiration proteins and the complex I were downregulated by SARS-CoV-2 infection [39] .…”

COVID‐19 metabolism: Mechanisms and therapeutic targets

“… 174 , 183 , 186 , 187 Notably, mPTP blocker cyclosporin A was demonstrated to protect cardiomyocytes from SARS‐CoV‐2‐induced autophagy and cell death. 183 …”

“… 182 Viral proteins ORF9c, M, Nsp6, and ORF3a were shown to localize to mitochondrial membrane and induce morphological changes. 183 Of note, viral proteins encoded by SARS‐CoV‐2 genome were reported to interact with multiple proteins located in mitochondrial inner membrane. Mitochondrial permeability transition pore (mPTP) is a protein complex formed in the inner membrane under specific pathological conditions.…”

“…Mechanistically, ORF9b promoted mitochondrial elongation by proteasomal degradation of dynamin‐related protein 1 (DRP1), a protein responsible for membrane remodeling during mitochondrial division 182 . Viral proteins ORF9c, M, Nsp6, and ORF3a were shown to localize to mitochondrial membrane and induce morphological changes 183 . Of note, viral proteins encoded by SARS‐CoV‐2 genome were reported to interact with multiple proteins located in mitochondrial inner membrane.…”

“…Viral proteins may hamper mitochondrial function through binding to mPTP and destructing mitochondrial inner membrane integrity. Depolarization of mitochondria could further impair mitophagy and cause apoptosis 174,183,186,187 . Notably, mPTP blocker cyclosporin A was demonstrated to protect cardiomyocytes from SARS‐CoV‐2‐induced autophagy and cell death 183 …”