Computational Discovery of Mitochondrial Dysfunction Biomarkers in Severe SARS-CoV-2 Infection: Unveiling Their Functions and Facilitating Drug Screening

29 Pages Posted: 29 Dec 2023

See all articles by Lihui Zhang

Lihui Zhang

Tianjin University of Traditional Chinese Medicine

Yuehan Li

Beijing Institute of Pharmacology and Toxicology

Wanting Hu

Beijing Institute of Pharmacology and Toxicology

Shengqiao Gao

Beijing Institute of Pharmacology and Toxicology

Yiran Tang

Beijing Institute of Pharmacology and Toxicology

Lei Sun

Beijing Institute of Pharmacology and Toxicology

Ning Jiang

Beijing Institute of Pharmacology and Toxicology

Zhiyong Xiao

Beijing Institute of Pharmacology and Toxicology

Lu Han

Beijing Institute of Pharmacology and Toxicology

Wenxia Zhou

Institute of Pharmacology and Toxicology - State Key Laboratory of Toxicology and Medical Countermeasures

Abstract

Background: Currently, SARS-CoV-2 has not disappeared and continues to prevail worldwide, with the ongoing risk of mutations and the potential for severe COVID-19. The impairment of monocyte mitochondrial function caused by SARS-CoV-2, leading to a metabolic and immune dysregulation, is a crucial factor in the development of severe COVID-19. The core biomarkers underlying the progression to severe SARS-CoV-2 infection and effective drugs remain unclear.Methods: Firstly, differential gene analysis and GSEA were conducted on monocytes datasets to identify genes and pathways distinguishing severe patients from uninfected individuals. Then, GO and KEGG enrichment analysis on the differentially expressed genes (DEGs) obtained. Take the DEGs and intersect them with the MitoCarta 3.0 gene set to obtain the differentially expressed mitochondrial-related genes (DE-MRGs). Subsequently, machine learning algorithms were employed to screen potential mitochondrial dysfunction biomarkers for severe COVID-19 based on score values. ROC curves were then plotted to assess the distinguish capability of the biomarkers, followed by validation using two additional independent datasets. Next, the effects of the identified biomarkers on metabolic pathways and immune cells were explored through Gene Set Variation Analysis (GSVA) and CIBERSORT. Finally, potential nature products for severe COVID-19 were screened from the expression profile dataset based on dysregulated mitochondrial-related genes, followed by in vitro experimental validation.Results: There are 1812 DEGs and 17 dysregulated mitochondrial processes between severe COVID-19 patients and uninfected individuals. A total of 77 DE-MRGs were identified, and the potential biomarkers were identified as RECQL4, PYCR1, PIF1, POLQ, and GLDC. In both the training and validation sets, the area under the ROC curve (AUC) for these five biomarkers was greater than 0.9. And they did not show significant changes in mild to moderate patients (P > 0.05), indicating their ability to effectively distinguish severe COVID-19. These biomarkers exhibit a highly significant correlation with the dysregulated metabolic processes (P < 0.05) and immune cell imbalance (P < 0.05) in severe patients, as demonstrated by GSVA and CIBERSORT algorithms. Curcumin has the highest score in the predictive model based on transcriptomic data from 496 natural compounds (P = 0.02; ES = 0.90). Pre-treatment with curcumin for 8 hours has been shown to alleviate mitochondrial membrane potential damage caused by the SARS-CoV-2 S1 protein (P < 0.05) and reduce elevated levels of reactive oxygen species (ROS) (P < 0.01). Conclusions: The results of this study indicate a significant correlation between severe SARS-CoV-2 infection and mitochondrial dysfunction. The proposed five mitochondrial dysfunction biomarkers identified in this study are associated with the disease progression, metabolic and immune changes in severe SARS-CoV-2 infected patients. Curcumin has a potential role in preventing severe COVID-19 by protecting mitochondrial function. Our findings provide new strategies for predicting prognosis and early intervention in severe SARS-CoV-2 infection.

Note:
Funding Information: This study was funded by the National Natural Science Foundation of China (82141218) and National Key Research and Development Program of China (2022YFC3500304).

Declaration of Interests: The authors declare no competing interests.

Keywords: SARS-CoV-2, Natural product, mitochondrial, COVID-19, biomarkers, Bioinformatics

Suggested Citation

Zhang, Lihui and Li, Yuehan and Hu, Wanting and Gao, Shengqiao and Tang, Yiran and Sun, Lei and Jiang, Ning and Xiao, Zhiyong and Han, Lu and Zhou, Wenxia, Computational Discovery of Mitochondrial Dysfunction Biomarkers in Severe SARS-CoV-2 Infection: Unveiling Their Functions and Facilitating Drug Screening. Available at SSRN: https://ssrn.com/abstract=4677176 or http://dx.doi.org/10.2139/ssrn.4677176

Lihui Zhang (Contact Author)

Tianjin University of Traditional Chinese Medicine ( email )

Yuehan Li

Beijing Institute of Pharmacology and Toxicology ( email )

Wanting Hu

Beijing Institute of Pharmacology and Toxicology ( email )

Shengqiao Gao

Beijing Institute of Pharmacology and Toxicology ( email )

Yiran Tang

Beijing Institute of Pharmacology and Toxicology ( email )

Lei Sun

Beijing Institute of Pharmacology and Toxicology ( email )

Ning Jiang

Beijing Institute of Pharmacology and Toxicology ( email )

Zhiyong Xiao

Beijing Institute of Pharmacology and Toxicology ( email )

Lu Han

Beijing Institute of Pharmacology and Toxicology ( email )

Wenxia Zhou

Institute of Pharmacology and Toxicology - State Key Laboratory of Toxicology and Medical Countermeasures ( email )

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