Pathway and Network Analyses Identify Growth Factor Signaling and MMP9 as Potential Mediators of Mitochondrial Dysfunction in Severe COVID-19

Ya Wang; Klaus Schughart; Tiana Maria Pelaia; Tracy Chew; Karan Kim; Thomas Karvunidis; Ben Knippenberg; Sally Teoh; Amy L Phu; Kirsty R Short; Jonathan Iredell; Irani Thevarajan; Jennifer Audsley; Stephen Macdonald; Jonathon Burcham; Predict-Consortium; Benjamin Tang; Anthony McLean; Maryam Shojaei

doi:10.3390/ijms24032524

Pathway and Network Analyses Identify Growth Factor Signaling and MMP9 as Potential Mediators of Mitochondrial Dysfunction in Severe COVID-19

Int J Mol Sci. 2023 Jan 28;24(3):2524. doi: 10.3390/ijms24032524.

Authors

Ya Wang^{1

2

3}, Klaus Schughart^{4

5}, Tiana Maria Pelaia¹, Tracy Chew⁶, Karan Kim², Thomas Karvunidis⁷, Ben Knippenberg⁸, Sally Teoh¹, Amy L Phu^{9

10}, Kirsty R Short¹¹, Jonathan Iredell^{12

13

14

15}, Irani Thevarajan^{16

17}, Jennifer Audsley¹⁷, Stephen Macdonald^{18

19

20}, Jonathon Burcham²¹, Predict-Consortium, Benjamin Tang^{1

2}, Anthony McLean^{1

3}, Maryam Shojaei^{1

2

3}

Affiliations

¹ Department of Intensive Care Medicine, Nepean Hospital, Kingswood, NSW 2747, Australia.
² Centre for Immunology and Allergy Research, The Westmead Institute for Medical Research, Sydney, NSW 2145, Australia.
³ Faculty of Medicine and Health, Sydney Medical School Nepean, Nepean Hospital, The University of Sydney, Kingswood, NSW 2747, Australia.
⁴ Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
⁵ Institute of Virology Münster, University of Münster, 48149 Münster, Germany.
⁶ Sydney Informatics Hub, Core Research Facilities, The University of Sydney, Sydney NSW 2006, Australia.
⁷ Medical ICU, 1st Department of Internal Medicine, Charles University and Teaching Hospital Pilsen, 323 00 Plzeň, Czech Republic.
⁸ Department of Microbiology, St. George Hospital, Sydney, NSW 2217, Australia.
⁹ Research and Education Network, Western Sydney Local Health District, Westmead Hospital, CNR Darcy and Hawkesbury Roads, Sydney, NSW 2145, Australia.
¹⁰ Faculty of Medicine and Health, Sydney Medical School Westmead, Westmead Hospital, The University of Sydney, Sydney, NSW 2145, Australia.
¹¹ School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD 4072, Australia.
¹² Centre for Infectious Diseases and Microbiology, The Westmead Institute for Medical Research, Sydney, NSW 2145, Australia.
¹³ Faculty of Medicine and Health, School of Medical Sciences, The University of Sydney, Sydney, NSW 2145, Australia.
¹⁴ Westmead Hospital, Western Sydney Local Health District, Sydney, NSW 2145, Australia.
¹⁵ Sydney Institute for Infectious Disease, The University of Sydney, Sydney, NSW 2145, Australia.
¹⁶ Victorian Infectious Disease Service, The Royal Melbourne Hospital at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3050, Australia.
¹⁷ Department of Infectious Diseases, The University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3000, Australia.
¹⁸ Centre for Clinical Research in Emergency Medicine, Harry Perkins Institute of Medical Research, Royal Perth Hospital, Perth, WA 6000, Australia.
¹⁹ Medical School, University of Western Australia, Perth, WA 6009, Australia.
²⁰ Emergency Department, Royal Perth Hospital, Perth, WA 6000, Australia.
²¹ Centre for Clinical Research in Emergency Medicine, Royal Perth Bentley Group, Perth, WA 6000, Australia.

Abstract

Patients with preexisting metabolic disorders such as diabetes are at a higher risk of developing severe coronavirus disease 2019 (COVID-19). Mitochondrion, the very organelle that controls cellular metabolism, holds the key to understanding disease progression at the cellular level. Our current study aimed to understand how cellular metabolism contributes to COVID-19 outcomes. Metacore pathway enrichment analyses on differentially expressed genes (encoded by both mitochondrial and nuclear deoxyribonucleic acid (DNA)) involved in cellular metabolism, regulation of mitochondrial respiration and organization, and apoptosis, was performed on RNA sequencing (RNASeq) data from blood samples collected from healthy controls and patients with mild/moderate or severe COVID-19. Genes from the enriched pathways were analyzed by network analysis to uncover interactions among them and up- or downstream genes within each pathway. Compared to the mild/moderate COVID-19, the upregulation of a myriad of growth factor and cell cycle signaling pathways, with concomitant downregulation of interferon signaling pathways, were observed in the severe group. Matrix metallopeptidase 9 (MMP9) was found in five of the top 10 upregulated pathways, indicating its potential as therapeutic target against COVID-19. In summary, our data demonstrates aberrant activation of endocrine signaling in severe COVID-19, and its implication in immune and metabolic dysfunction.

Keywords: COVID-19; DEG; MMP9; Metacore; RNA sequencing; endocrine; metabolism.

MeSH terms

COVID-19*
Humans
Intercellular Signaling Peptides and Proteins
Matrix Metalloproteinase 9 / genetics
Matrix Metalloproteinase 9 / metabolism
Mitochondria / metabolism
Signal Transduction

Substances

Matrix Metalloproteinase 9
Intercellular Signaling Peptides and Proteins
MMP9 protein, human

Abstract

MeSH terms

Substances

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