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.

Centre for Clinical Research in Emergency Medicine Harry Perkins Institute of Medical Research Royal Perth Hospital Perth WA 6000 Australia

Centre for Clinical Research in Emergency Medicine Royal Perth Bentley Group Perth WA 6000 Australia

Centre for Immunology and Allergy Research The Westmead Institute for Medical Research Sydney NSW 2145 Australia

Centre for Infectious Diseases and Microbiology The Westmead Institute for Medical Research Sydney NSW 2145 Australia

Department of Infectious Diseases The University of Melbourne at the Peter Doherty Institute for Infection and Immunity Melbourne VIC 3000 Australia

Department of Intensive Care Medicine Nepean Hospital Kingswood NSW 2747 Australia

Department of Microbiology Immunology and Biochemistry University of Tennessee Health Science Center Memphis TN 38163 USA

Department of Microbiology St George Hospital Sydney NSW 2217 Australia

Emergency Department Royal Perth Hospital Perth WA 6000 Australia

Faculty of Medicine and Health School of Medical Sciences The University of Sydney Sydney NSW 2145 Australia

Faculty of Medicine and Health Sydney Medical School Nepean Nepean Hospital The University of Sydney Kingswood NSW 2747 Australia

Faculty of Medicine and Health Sydney Medical School Westmead Westmead Hospital The University of Sydney Sydney NSW 2145 Australia

Institute of Virology Münster University of Münster 48149 Münster Germany

Medical ICU 1st Department of Internal Medicine Charles University and Teaching Hospital Pilsen 323 00 Plzeň Czech Republic

Medical School University of Western Australia Perth WA 6009 Australia

Research and Education Network Western Sydney Local Health District Westmead Hospital CNR Darcy and Hawkesbury Roads Sydney NSW 2145 Australia

School of Chemistry and Molecular Biosciences The University of Queensland Brisbane QLD 4072 Australia

Sydney Informatics Hub Core Research Facilities The University of Sydney Sydney NSW 2006 Australia

Sydney Institute for Infectious Disease The University of Sydney Sydney NSW 2145 Australia

Victorian Infectious Disease Service The Royal Melbourne Hospital at the Peter Doherty Institute for Infection and Immunity Melbourne VIC 3050 Australia

Westmead Hospital Western Sydney Local Health District Sydney NSW 2145 Australia

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