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

被引：37

作者：

Archer, Stephen L. ^{[1
,2
,9
]}

Dasgupta, Asish ^{[1
]}

Chen, Kuang-Hueih ^{[1
]}

Wu, Danchen ^{[1
]}

Baid, Kaushal ^{[3
]}

Mamatis, John E. ^{[4
]}

Gonzalez, Victoria ^{[3
,5
]}

Read, Austin ^{[1
]}

Bentley, Rachel ET. ^{[1
]}

Martin, Ashley Y. ^{[1
]}

Mewburn, Jeffrey D. ^{[1
]}

Dunham-Snary, Kimberly J. ^{[1
,4
]}

Evans, Gerald A. ^{[1
]}

Levy, Gary ^{[6
]}

Jones, Oliver ^{[2
]}

Al-Qazazi, Ruaa ^{[1
]}

Ring, Brooke ^{[2
]}

Alizadeh, Elahe ^{[2
]}

Hindmarch, Charles CT. ^{[2
]}

Rossi, Jenna ^{[1
]}

Lima, Patricia DA. ^{[2
]}

Falzarano, Darryl ^{[3
,5
]}

Banerjee, Arinjay ^{[5
,7
,8
]}

Colpitts, Che C. ^{[4
]}

机构：

[1] Queens Univ, Dept Med, Kingston, ON, Canada

[2] Queens Univ, Queens Cardiopulm Unit QCPU, Kingston, ON, Canada

[3] Univ Saskatchewan, Vaccine & Infect Dis Org, Saskatoon, SK, Canada

[4] Queens Univ, Dept Biomed & Mol Sci, Kingston, ON, Canada

[5] Univ Saskatchewan, Western Coll Vet Med, Dept Vet Microbiol, Saskatoon, SK, Canada

[6] Univ Toronto, Toronto, ON, Canada

[7] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON, Canada

[8] Univ Waterloo, Dept Biol, Waterloo, ON, Canada

[9] Queens Univ Etherington Hall, Head Dept Med, Room 3041 94 Stuart St, Kingston, ON K7L 3N6, Canada

来源：

REDOX BIOLOGY | 2022年 / 58卷

基金：

加拿大自然科学与工程研究理事会; 美国国家卫生研究院; 加拿大创新基金会;

关键词：

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); ACUTE RESPIRATORY SYNDROME; CORONAVIRUS OC43; APOPTOSIS; DISEASE; PROTEIN; PROLIFERATION; INFECTIONS; INHIBITORS; SUBUNIT; VIRUSES;

D O I：

10.1016/j.redox.2022.102508

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 indi-vidual 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 pneu-monia, 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 hypox-emia and constitutes a therapeutic target.

引用

页数：21

共 64 条

[1] Gene expression and in situ protein profiling of candidate SARS-CoV-2 receptors in human airway epithelial cells and lung tissue [J].

Aguiar, Jennifer A. ;

Tremblay, Benjamin J-M ;

Mansfield, Michael J. ;

Woody, Owen ;

Lobb, Briallen ;

Banerjee, Arinjay ;

Chandiramohan, Abiram ;

Tiessen, Nicholas ;

Cao, Quynh ;

Dvorkin-Gheva, Anna ;

Revill, Spencer ;

Miller, Matthew S. ;

Carlsten, Christopher ;

Organ, Louise ;

Joseph, Chitra ;

John, Alison ;

Hanson, Paul ;

Austin, Richard C. ;

McManus, Bruce M. ;

Jenkins, Gisli ;

Mossman, Karen ;

Ask, Kjetil ;

Doxey, Andrew C. ;

Hirota, Jeremy A. .

EUROPEAN RESPIRATORY JOURNAL, 2020, 56 (03)

[2]

[Anonymous], 2022, COVID 19 RESOURCES C

[3] HYPOXIC PULMONARY VASOCONSTRICTION IS ENHANCED BY INHIBITION OF THE SYNTHESIS OF AN ENDOTHELIUM DERIVED RELAXING FACTOR [J].

ARCHER, SL ;

TOLINS, JP ;

RAIJ, L ;

WEIR, EK .

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1989, 164 (03) :1198-1205

[4] Differentiating COVID-19 Pneumonia From Acute Respiratory Distress Syndrome and High Altitude Pulmonary Edema Therapeutic Implications [J].

Archer, Stephen L. ;

Sharp, Willard W. ;

Weir, E. Kenneth .

CIRCULATION, 2020, 142 (02) :101-104

[5] Experimental and natural evidence of SARS-CoV-2-infection-induced activation of type I interferon responses [J].

Banerjee, Arinjay ;

El-Sayes, Nader ;

Budylowski, Patrick ;

Jacob, Rajesh Abraham ;

Richard, Daniel ;

Maan, Hassaan ;

Aguiar, Jennifer A. ;

Demian, Wael L. ;

Baid, Kaushal ;

D'Agostino, Michael R. ;

Ang, Jann Catherine ;

Murdza, Tetyana ;

Tremblay, Benjamin J-M ;

Afkhami, Sam ;

Karimzadeh, Mehran ;

Irving, Aaron T. ;

Yip, Lily ;

Ostrowski, Mario ;

Hirota, Jeremy A. ;

Kozak, Robert ;

Capellini, Terence D. ;

Miller, Matthew S. ;

Wang, Bo ;

Mubareka, Samira ;

McGeer, Allison J. ;

McArthur, Andrew G. ;

Doxey, Andrew C. ;

Mossman, Karen .

ISCIENCE, 2021, 24 (05)

[6] Isolation, Sequence, Infectivity and Replication Kinetics of Severe Acute Respiratory Syndrome Coronavirus 2 [J].

Banerjee, Arinjay ;

Nasir, Jalees A. ;

Budylowski, Patrick ;

Yip, Lily ;

Aftanas, Patryk ;

Christie, Natasha ;

Ghalami, Ayoob ;

Baid, Kaushal ;

Raphenya, Amogelang R. ;

Hirota, Jeremy A. ;

Miller, Matthew S. ;

McGeer, Allison J. ;

Ostrowski, Mario ;

Kozak, Robert A. ;

McArthur, Andrew G. ;

Mossman, Karen ;

Mubareka, Samira .

EMERGING INFECTIOUS DISEASES, 2020, 26 (09) :2054-2063

[7]

BEE D, 1983, B EUR PHYSIOPATH RES, V19, P539

[8] The paradoxical pro- and anti-apoptotic actions of GSK3 in the intrinsic and extrinsic apoptosis signaling pathways [J].

Beurel, Eleonore ;

Jope, Richard S. .

PROGRESS IN NEUROBIOLOGY, 2006, 79 (04) :173-189

[9] Cadmium induced BEAS-2B cells apoptosis and mitochondria damage via MAPK signaling pathway [J].

Cao, Xiangyu ;

Fu, Mingyang ;

Bi, Ruochen ;

Zheng, Xiaomei ;

Fu, Baorong ;

Tian, Siqi ;

Liu, Chengying ;

Li, Qijiu ;

Liu, Jianli .

CHEMOSPHERE, 2021, 263

[10] Haemodynamic characteristics of COVID-19 patients with acute respiratory distress syndrome requiring mechanical ventilation. An invasive assessment using right heart catheterization [J].

Caravita, Sergio ;

Baratto, Claudia ;

Di Marco, Fabiano ;

Calabrese, Alice ;

Balestrieri, Giulio ;

Russo, Filippo ;

Faini, Andrea ;

Soranna, Davide ;

Perego, Giovanni Battista ;

Badano, Luigi P. ;

Grazioli, Lorenzo ;

Lorini, Ferdinando Luca ;

Parati, Gianfranco ;

Senni, Michele .

EUROPEAN JOURNAL OF HEART FAILURE, 2020, 22 (12) :2228-2237

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