@article{ffcbc05936154818b71793c20a28e693,
title = "Pathway and Network Analyses Identify Growth Factor Signaling and MMP9 as Potential Mediators of Mitochondrial Dysfunction in Severe COVID-19",
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, endocrine, metabolism, Metacore, MMP9, RNA sequencing",
author = "{PREDICT-19 Consortium} and Ya Wang and Klaus Schughart and Pelaia, {Tiana Maria} and Tracy Chew and Karan Kim and Thomas Karvunidis and Ben Knippenberg and Sally Teoh and Phu, {Amy L.} and Short, {Kirsty R.} and Jonathan Iredell and Irani Thevarajan and Jennifer Audsley and Stephen Macdonald and Jonathon Burcham and Benjamin Tang and Anthony McLean and Maryam Shojaei",
note = "Funding Information: This study was funded by Snow Medical Research Foundation (BEAT COVID-19), the National Health and Medical Research Council (Australian Partnership for Preparedness Research on Infectious Disease Emergencies (APPRISE AppID 1116530)), the Jack Ma Foundation, and the A2 Milk Company. This study was also supported by intramural grants from the Helmholtz-Association: intramural funding; University of Tennessee Health Science Center: intramural funding; NIAID: 5U19A|100625-07; NIAID: 2-U19-AI100625-06 awarded to KS. K.R.S. is supported by NHMRC investigator grant 2007919. Funding Information: We thank all participants involved in this study. This research included samples and data from the Sentinel Travelers Research Preparedness Platform for Emerging Infectious Diseases (SETREP-ID). The authors acknowledge SETREP-ID investigators and sites. The authors acknowledge the Sydney Informatics Hub, a Core Research Facility at the University of Sydney and the Australian BioCommons for access to bioinformatics expertise and computational resources. The data was preprocessed with these resources on the National Computational Infrastructure (NCI) supported by the Australian Government and the Sydney Informatics Hub HPC Allocation Scheme. The authors wish to acknowledge Marie Everest for assisting in the wet lab workflows, and Christopher Noune for reviewing sequencing methods for Australian Genomics Research Facility (AGRF) supported by the Australian Government National Collaborative Research Infrastructure Initiative through Bioplatforms Australia. QC of RNA samples were performed by Joey Lai at the Westmead Scientific Platforms, which are supported by the Westmead Research Hub, the Cancer Institute New South Wales, the National Health and Medical Research Council and the Ian Potter Foundation. Publisher Copyright: {\textcopyright} 2023 by the authors.",
year = "2023",
month = feb,
doi = "10.3390/ijms24032524",
language = "English",
volume = "24",
journal = "International Journal of Molecular Sciences",
issn = "1661-6596",
publisher = "MDPI AG",
number = "3",
}