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 D.; Bentley, Rachel ET.; Martin, Ashley Y.; Mewburn, Jeffrey D.; Dunham-Snary, Kimberly J.; Evans, Gerald A; Levy, Gary J.; Jones, Oliver William; Al-Qazazi, Ruaa; Ring, Brooke A.; Alizadeh, Elahe; Hindmarch, Charles CT.; Rossi, Jenna; Lima, Patricia DA.; Falzarano, Darryl; Banerjee, Arinjay; Colpitts, Che C

doi:10.1016/j.redox.2022.102508

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

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

Publication date (Electronic): 13 October 2022

Journal: Redox Biology

Publisher: The Author(s). Published by Elsevier B.V.

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

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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 beta coronaviruses, 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 h 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 SpO ₂.

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.

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Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2

Michael Love, Wolfgang Huber, Simon Anders (2014)

In comparative high-throughput sequencing assays, a fundamental task is the analysis of count data, such as read counts per gene in RNA-seq, for evidence of systematic changes across experimental conditions. Small replicate numbers, discreteness, large dynamic range and the presence of outliers require a suitable statistical approach. We present DESeq2, a method for differential analysis of count data, using shrinkage estimation for dispersions and fold changes to improve stability and interpretability of estimates. This enables a more quantitative analysis focused on the strength rather than the mere presence of differential expression. The DESeq2 package is available at http://www.bioconductor.org/packages/release/bioc/html/DESeq2.html. Electronic supplementary material The online version of this article (doi:10.1186/s13059-014-0550-8) contains supplementary material, which is available to authorized users.

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Clinical Characteristics of Coronavirus Disease 2019 in China

Wei-jie Guan, Zheng-yi Ni, Yu Hu … (2020)

Abstract Background Since December 2019, when coronavirus disease 2019 (Covid-19) emerged in Wuhan city and rapidly spread throughout China, data have been needed on the clinical characteristics of the affected patients. Methods We extracted data regarding 1099 patients with laboratory-confirmed Covid-19 from 552 hospitals in 30 provinces, autonomous regions, and municipalities in mainland China through January 29, 2020. The primary composite end point was admission to an intensive care unit (ICU), the use of mechanical ventilation, or death. Results The median age of the patients was 47 years; 41.9% of the patients were female. The primary composite end point occurred in 67 patients (6.1%), including 5.0% who were admitted to the ICU, 2.3% who underwent invasive mechanical ventilation, and 1.4% who died. Only 1.9% of the patients had a history of direct contact with wildlife. Among nonresidents of Wuhan, 72.3% had contact with residents of Wuhan, including 31.3% who had visited the city. The most common symptoms were fever (43.8% on admission and 88.7% during hospitalization) and cough (67.8%). Diarrhea was uncommon (3.8%). The median incubation period was 4 days (interquartile range, 2 to 7). On admission, ground-glass opacity was the most common radiologic finding on chest computed tomography (CT) (56.4%). No radiographic or CT abnormality was found in 157 of 877 patients (17.9%) with nonsevere disease and in 5 of 173 patients (2.9%) with severe disease. Lymphocytopenia was present in 83.2% of the patients on admission. Conclusions During the first 2 months of the current outbreak, Covid-19 spread rapidly throughout China and caused varying degrees of illness. Patients often presented without fever, and many did not have abnormal radiologic findings. (Funded by the National Health Commission of China and others.)

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clusterProfiler: an R package for comparing biological themes among gene clusters.

Guangchuang Yu, Li-Gen Wang, Yanyan Han … (2012)

Increasing quantitative data generated from transcriptomics and proteomics require integrative strategies for analysis. Here, we present an R package, clusterProfiler that automates the process of biological-term classification and the enrichment analysis of gene clusters. The analysis module and visualization module were combined into a reusable workflow. Currently, clusterProfiler supports three species, including humans, mice, and yeast. Methods provided in this package can be easily extended to other species and ontologies. The clusterProfiler package is released under Artistic-2.0 License within Bioconductor project. The source code and vignette are freely available at http://bioconductor.org/packages/release/bioc/html/clusterProfiler.html.

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Author and article information

Journal

Journal ID (nlm-ta): Redox Biol

Journal ID (iso-abbrev): Redox Biol

Title: Redox Biology

Publisher: The Author(s). Published by Elsevier B.V.

ISSN (Electronic): 2213-2317

Publication date PMC-release: 13 October 2022

Publication date (Electronic): 13 October 2022

Electronic Location Identifier: 102508

Affiliations

[a ]Department of Medicine, Queen’s University, Kingston, ON, Canada

[b ]Queen’s Cardiopulmonary Unit (QCPU), Queen’s University, Kingston, ON, Canada

[c ]Vaccine and Infectious Disease Organization, University of Saskatchewan, Saskatoon, SK, Canada

[d ]Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, ON, Canada

[e ]Department of Veterinary Microbiology, Western College of Veterinary Medicine, University of Saskatchewan; Saskatoon, SK, Canada

[f ]University of Toronto, Toronto, ON, Canada

[g ]Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada

[h ]Department of Biology, University of Waterloo; Waterloo, ON, Canada

Author notes

[∗ ]Corresponding author. Head Department of Medicine, Queen's University Etherington Hall, Room 3041 94 Stuart St., Kingston, Ontario, K7L 3N6, Canada.

Article

Publisher Item ID: S2213-2317(22)00280-4 Publisher ID: 102508

DOI: 10.1016/j.redox.2022.102508

PMC ID: 9558649

PubMed ID: 36334378

SO-VID: bc3e2b10-a53b-4c78-9742-0c5d7df70ce4

License:

Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

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

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Abstract

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Graphical abstract

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Novel Coronavirus Disease COVID-19

Most cited references 64

Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2

Clinical Characteristics of Coronavirus Disease 2019 in China

clusterProfiler: an R package for comparing biological themes among gene clusters.

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