Metabolic and mitochondria alterations induced by SARS-CoV-2 accessory proteins ORF3a, ORF9b, ORF9c and ORF10

Lopez-Ayllon, B. D.; Marin, S.; Farinas Fernandez, M.; Garcia-Garcia, T.; Fernandez-Rodriguez, R.; de Lucas-Rius, A.; Redondo, N.; Mendoza-Garcia, L.; Foguet, C.; Grigas, J.; Calvet, A.; Villalba, J. M.; Rodriguez Gomez, M. J.; Megias, D.; Mandracchia, B.; Luque, D.; Lozano, J. J.; Calvo, C.; Thomson, T. M.; Garrido, J. J.; Cascante, M.; Montoya, M.

doi:10.1101/2023.09.26.559506

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bioRxiv · 10.1101/2023.09.26.559506

Metabolic and mitochondria alterations induced by SARS-CoV-2 accessory proteins ORF3a, ORF9b, ORF9c and ORF10

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Abstract

Antiviral signaling, immune response and cell metabolism in human body are dysregulated by SARS-CoV-2, the causative agent of the COVID-19. Here, we show that SARS-CoV-2 accessory proteins ORF3a, ORF9b, ORF9c and ORF10 induce a significant mitochondrial and metabolic reprogramming in A549 lung epithelial cells. While all four ORFs caused mitochondrial fragmentation and altered mitochondrial function, only ORF3a and ORF9c induced a marked structural alteration in mitochondrial cristae. ORF9b, ORF9c and ORF10 induced largely overlapping transcriptomes. In contrast, ORF3a induced a distinct transcriptome, including the downregulation of numerous genes for proteins with critical mitochondrial functions and morphology. Genome-Scale Metabolic Models predicted common and private metabolic flux reprogramming, notably a depressed amino acid metabolism, and an enhanced metabolism of specific lipids distinctly induced by ORF3a. These findings reveal metabolic dependencies and vulnerabilities prompted by SARS-CoV-2 accessory proteins that may be exploited to identify new targets for intervention. One-Sentence SummaryMitochondria and metabolic alterations induced by SARS- CoV-2 accessory proteins ORF3a, ORF9b, ORF9c, ORF10 in pulmonary cells unravel new targets of intervention.

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Lopez-Ayllon, B. D., Marin, S., Farinas Fernandez, M., Garcia-Garcia, T., Fernandez-Rodriguez, R., de Lucas-Rius, A., Redondo, N., Mendoza-Garcia, L., Foguet, C., Grigas, J., Calvet, A., Villalba, J. M., Rodriguez Gomez, M. J., Megias, D., Mandracchia, B., Luque, D., Lozano, J. J., Calvo, C., Thomson, T. M., Garrido, J. J., Cascante, M., Montoya, M.. 2023-09-26. Metabolic and mitochondria alterations induced by SARS-CoV-2 accessory proteins ORF3a, ORF9b, ORF9c and ORF10. https://doi.org/10.1101/2023.09.26.559506

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