Your browser doesn't support javascript.
SARS-CoV-2 mitochondriopathy in COVID-19 pneumonia exacerbates hypoxemia.
Archer, Stephen L; Dasgupta, Asish; Chen, Kuang-Hueih; Wu, Danchen; Baid, Kaushal; Mamatis, John E; Gonzalez, Victoria; Read, Austin; Bentley, Rachel Et; Martin, Ashley Y; Mewburn, Jeffrey D; Dunham-Snary, Kimberly J; Evans, Gerald A; Levy, Gary; Jones, Oliver; Al-Qazazi, Ruaa; Ring, Brooke; Alizadeh, Elahe; Hindmarch, Charles Ct; Rossi, Jenna; Lima, Patricia DA; Falzarano, Darryl; Banerjee, Arinjay; Colpitts, Che C.
  • Archer SL; 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.
  • Dasgupta A; Department of Medicine, Queen's University, Kingston, ON, Canada.
  • Chen KH; Department of Medicine, Queen's University, Kingston, ON, Canada.
  • Wu D; Department of Medicine, Queen's University, Kingston, ON, Canada.
  • Baid K; Vaccine and Infectious Disease Organization, University of Saskatchewan, Saskatoon, SK, Canada.
  • Mamatis JE; Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada.
  • Gonzalez V; 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.
  • Read A; Department of Medicine, Queen's University, Kingston, ON, Canada.
  • Bentley RE; Department of Medicine, Queen's University, Kingston, ON, Canada.
  • Martin AY; Department of Medicine, Queen's University, Kingston, ON, Canada.
  • Mewburn JD; Department of Medicine, Queen's University, Kingston, ON, Canada.
  • Dunham-Snary KJ; Department of Medicine, Queen's University, Kingston, ON, Canada; Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada.
  • Evans GA; Department of Medicine, Queen's University, Kingston, ON, Canada.
  • Levy G; University of Toronto, Toronto, ON, Canada.
  • Jones O; Queen's Cardiopulmonary Unit (QCPU), Queen's University, Kingston, ON, Canada.
  • Al-Qazazi R; Department of Medicine, Queen's University, Kingston, ON, Canada.
  • Ring B; Queen's Cardiopulmonary Unit (QCPU), Queen's University, Kingston, ON, Canada.
  • Alizadeh E; Queen's Cardiopulmonary Unit (QCPU), Queen's University, Kingston, ON, Canada.
  • Hindmarch CC; Queen's Cardiopulmonary Unit (QCPU), Queen's University, Kingston, ON, Canada.
  • Rossi J; Department of Medicine, Queen's University, Kingston, ON, Canada.
  • Lima PD; Queen's Cardiopulmonary Unit (QCPU), Queen's University, Kingston, ON, Canada.
  • Falzarano D; 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.
  • Banerjee A; 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,
  • Colpitts CC; Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada.
Redox Biol ; 58: 102508, 2022 Dec.
Article in English | MEDLINE | ID: covidwho-2069622
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.
Subject(s)
Keywords
Fulltext
Print
XML
PubMed Links
Search on Google

Full text: Available Collection: International databases Database: MEDLINE Main subject: Papillomavirus Infections / COVID-19 Topics: Long Covid Limits: Animals / Humans Language: English Journal: Redox Biol Year: 2022 Document Type: Article

Similar

MEDLINE
LILACS
LIS
Fulltext
Print
XML
PubMed Links
Search on Google

Full text: Available Collection: International databases Database: MEDLINE Main subject: Papillomavirus Infections / COVID-19 Topics: Long Covid Limits: Animals / Humans Language: English Journal: Redox Biol Year: 2022 Document Type: Article