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

doi:10.1016/j.redox.2022.102508

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

Redox Biol. 2022 Dec:58:102508. doi: 10.1016/j.redox.2022.102508. Epub 2022 Oct 13.

Authors

Stephen L Archer¹, Asish Dasgupta², Kuang-Hueih Chen², Danchen Wu², Kaushal Baid³, John E Mamatis⁴, Victoria Gonzalez⁵, Austin Read², Rachel Et Bentley², Ashley Y Martin², Jeffrey D Mewburn², Kimberly J Dunham-Snary⁶, Gerald A Evans², Gary Levy⁷, Oliver Jones⁸, Ruaa Al-Qazazi², Brooke Ring⁸, Elahe Alizadeh⁸, Charles Ct Hindmarch⁸, Jenna Rossi², Patricia DA Lima⁸, Darryl Falzarano⁵, Arinjay Banerjee⁹, Che C Colpitts⁴

Affiliations

¹ Department of Medicine, Queen's University, Kingston, ON, Canada; Queen's Cardiopulmonary Unit (QCPU), Queen's University, Kingston, ON, Canada. Electronic address: stephen.archer@queensu.ca.
² Department of Medicine, Queen's University, Kingston, ON, Canada.
³ Vaccine and Infectious Disease Organization, University of Saskatchewan, Saskatoon, SK, Canada.
⁴ Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada.
⁵ 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.
⁶ Department of Medicine, Queen's University, Kingston, ON, Canada; Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada.
⁷ University of Toronto, Toronto, ON, Canada.
⁸ Queen's Cardiopulmonary Unit (QCPU), Queen's University, Kingston, ON, Canada.
⁹ 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.

Abstract

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.

Keywords: Apoptosis; Apoptosis inducing factor (AIF); Dynamin related protein 1 (Drp1); HCoV-OC43; Hypoxic pulmonary vasoconstriction; Mitochondrial fission; Mitochondrial permeability transition pore (mPTP); Murine hepatitis virus (MHV-1).

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adenosine Triphosphate
Animals
COVID-19*
Humans
Hypoxia / complications
Mice
Mitochondrial Permeability Transition Pore
Papillomavirus Infections*
SARS-CoV-2

Substances

Mitochondrial Permeability Transition Pore
Adenosine Triphosphate

Abstract

Publication types

MeSH terms

Substances

Grants and funding