SARS-CoV-2 mitochondriopathy in COVID-19 pneumonia exacerbates hypoxemia

Stephen L. Archer; Asish Dasgupta; Kuang-Hueih Chen; Danchen Wu; Kaushal Baid; John E. Mamatis; Victoria Gonzalez; Austin Read; Rachel ET. Bentley; Ashley Y. Martin; Jeffrey D. Mewburn; Kimberly J. Dunham-Snary; Gerald A. Evans; Gary Levy; Oliver Jones; Ruaa Al-Qazazi; Brooke Ring; Elahe Alizadeh; Charles CT. Hindmarch; Jenna Rossi; Patricia DA. Lima; Darryl Falzarano; Arinjay Banerjee; Che C. Colpitts

Redox Biology (Dec 2022)

SARS-CoV-2 mitochondriopathy in COVID-19 pneumonia exacerbates hypoxemia

Stephen L. Archer,
Asish Dasgupta,
Kuang-Hueih Chen,
Danchen Wu,
Kaushal Baid,
John E. Mamatis,
Victoria Gonzalez,
Austin Read,
Rachel ET. Bentley,
Ashley Y. Martin,
Jeffrey D. Mewburn,
Kimberly J. Dunham-Snary,
Gerald A. Evans,
Gary Levy,
Oliver Jones,
Ruaa Al-Qazazi,
Brooke Ring,
Elahe Alizadeh,
Charles CT. Hindmarch,
Jenna Rossi,
Patricia DA. Lima,
Darryl Falzarano,
Arinjay Banerjee,
Che C. Colpitts

Affiliations

Stephen L. Archer: Department of Medicine, Queen’s University, Kingston, ON, Canada; Queen’s Cardiopulmonary Unit (QCPU), Queen’s University, Kingston, ON, Canada; Corresponding author. Head Department of Medicine, Queen's University Etherington Hall, Room 3041 94 Stuart St., Kingston, Ontario, K7L 3N6, Canada.
Asish Dasgupta: Department of Medicine, Queen’s University, Kingston, ON, Canada
Kuang-Hueih Chen: Department of Medicine, Queen’s University, Kingston, ON, Canada
Danchen Wu: Department of Medicine, Queen’s University, Kingston, ON, Canada
Kaushal Baid: Vaccine and Infectious Disease Organization, University of Saskatchewan, Saskatoon, SK, Canada
John E. Mamatis: Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, ON, Canada
Victoria Gonzalez: Vaccine and Infectious Disease Organization, University of Saskatchewan, Saskatoon, SK, Canada; Department of Veterinary Microbiology, Western College of Veterinary Medicine, University of Saskatchewan; Saskatoon, SK, Canada
Austin Read: Department of Medicine, Queen’s University, Kingston, ON, Canada
Rachel ET. Bentley: Department of Medicine, Queen’s University, Kingston, ON, Canada
Ashley Y. Martin: Department of Medicine, Queen’s University, Kingston, ON, Canada
Jeffrey D. Mewburn: Department of Medicine, Queen’s University, Kingston, ON, Canada
Kimberly J. Dunham-Snary: Department of Medicine, Queen’s University, Kingston, ON, Canada; Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, ON, Canada
Gerald A. Evans: Department of Medicine, Queen’s University, Kingston, ON, Canada
Gary Levy: University of Toronto, Toronto, ON, Canada
Oliver Jones: Queen’s Cardiopulmonary Unit (QCPU), Queen’s University, Kingston, ON, Canada
Ruaa Al-Qazazi: Department of Medicine, Queen’s University, Kingston, ON, Canada
Brooke Ring: Queen’s Cardiopulmonary Unit (QCPU), Queen’s University, Kingston, ON, Canada
Elahe Alizadeh: Queen’s Cardiopulmonary Unit (QCPU), Queen’s University, Kingston, ON, Canada
Charles CT. Hindmarch: Queen’s Cardiopulmonary Unit (QCPU), Queen’s University, Kingston, ON, Canada
Jenna Rossi: Department of Medicine, Queen’s University, Kingston, ON, Canada
Patricia DA. Lima: Queen’s Cardiopulmonary Unit (QCPU), Queen’s University, Kingston, ON, Canada
Darryl Falzarano: Vaccine and Infectious Disease Organization, University of Saskatchewan, Saskatoon, SK, Canada; Department of Veterinary Microbiology, Western College of Veterinary Medicine, University of Saskatchewan; Saskatoon, SK, Canada
Arinjay Banerjee: Vaccine and Infectious Disease Organization, University of Saskatchewan, Saskatoon, SK, Canada; Department of Veterinary Microbiology, Western College of Veterinary Medicine, University of Saskatchewan; Saskatoon, SK, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Department of Biology, University of Waterloo; Waterloo, ON, Canada
Che C. Colpitts: Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, ON, Canada

Journal volume & issue: Vol. 58
p. 102508

Abstract

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Rationale: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19 pneumonia. We hypothesize that SARS-CoV-2 causes alveolar injury and hypoxemia by damaging mitochondria in airway epithelial cells (AEC) and pulmonary artery smooth muscle cells (PASMC), triggering apoptosis and bioenergetic impairment, and impairing hypoxic pulmonary vasoconstriction (HPV), respectively. Objectives: We examined the effects of: A) human betacoronaviruses, SARS-CoV-2 and HCoV-OC43, and individual SARS-CoV-2 proteins on apoptosis, mitochondrial fission, and bioenergetics in AEC; and B) SARS-CoV-2 proteins and mouse hepatitis virus (MHV-1) infection on HPV. Methods: We used transcriptomic data to identify temporal changes in mitochondrial-relevant gene ontology (GO) pathways post-SARS-CoV-2 infection. We also transduced AECs with SARS-CoV-2 proteins (M, Nsp7 or Nsp9) and determined effects on mitochondrial permeability transition pore (mPTP) activity, relative membrane potential, apoptosis, mitochondrial fission, and oxygen consumption rates (OCR). In human PASMC, we assessed the effects of SARS-CoV-2 proteins on hypoxic increases in cytosolic calcium, an HPV proxy. In MHV-1 pneumonia, we assessed HPV via cardiac catheterization and apoptosis using the TUNEL assay. Results: SARS-CoV-2 regulated mitochondrial apoptosis, mitochondrial membrane permeabilization and electron transport chain (ETC) GO pathways within 2 hours of infection. SARS-CoV-2 downregulated ETC Complex I and ATP synthase genes, and upregulated apoptosis-inducing genes. SARS-CoV-2 and HCoV-OC43 upregulated and activated dynamin-related protein 1 (Drp1) and increased mitochondrial fission. SARS-CoV-2 and transduced SARS-CoV-2 proteins increased apoptosis inducing factor (AIF) expression and activated caspase 7, resulting in apoptosis. Coronaviruses also reduced OCR, decreased ETC Complex I activity and lowered ATP levels in AEC. M protein transduction also increased mPTP opening. In human PASMC, M and Nsp9 proteins inhibited HPV. In MHV-1 pneumonia, infected AEC displayed apoptosis and HPV was suppressed. BAY K8644, a calcium channel agonist, increased HPV and improved SpO2. Conclusions: Coronaviruses, including SARS-CoV-2, cause AEC apoptosis, mitochondrial fission, and bioenergetic impairment. SARS-CoV-2 also suppresses HPV by targeting mitochondria. This mitochondriopathy is replicated by transduction with SARS-CoV-2 proteins, indicating a mechanistic role for viral-host mitochondrial protein interactions. Mitochondriopathy is a conserved feature of coronaviral pneumonia that may exacerbate hypoxemia and constitutes a therapeutic target.

Published in Redox Biology

ISSN: 2213-2317 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Medicine (General); Science: Biology (General)
Website: http://www.journals.elsevier.com/redox-biology/

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