tetano
Editor, Senior Moderator
J Med Virol
. 2024 Jul;96(7):e29752.
doi: 10.1002/jmv.29752. Metabolic and mitochondria alterations induced by SARS-CoV-2 accessory proteins ORF3a, ORF9b, ORF9c and ORF10
Blanca D López-Ayllón[SUP] 1 [/SUP], Silvia Marin[SUP] 2 3 4 [/SUP], Marco Fariñas Fernández[SUP] 2 5 [/SUP], Tránsito García-García[SUP] 6 7 [/SUP], Raúl Fernández-Rodríguez[SUP] 6 7 [/SUP], Ana de Lucas-Rius[SUP] 1 [/SUP], Natalia Redondo[SUP] 8 9 [/SUP], Laura Mendoza-García[SUP] 1 [/SUP], Carles Foguet[SUP] 10 [/SUP], Juozas Grigas[SUP] 11 12 [/SUP], Alba Calvet[SUP] 2 4 [/SUP], José Manuel Villalba[SUP] 13 [/SUP], María Josefa Rodríguez Gómez[SUP] 14 15 [/SUP], Diego Megías[SUP] 14 [/SUP], Biagio Mandracchia[SUP] 14 16 [/SUP], Daniel Luque[SUP] 14 17 18 [/SUP], Juan José Lozano[SUP] 3 [/SUP], Cristina Calvo[SUP] 19 [/SUP], Unai Merino Herrán[SUP] 1 [/SUP], Timothy M Thomson[SUP] 3 19 20 [/SUP], Juan J Garrido[SUP] 6 7 [/SUP], Marta Cascante[SUP] 2 3 4 [/SUP], María Montoya[SUP] 1 [/SUP]
Affiliations
Antiviral signaling, immune response and cell metabolism are dysregulated by SARS-CoV-2, the causative agent of 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 ORF9b, ORF9c and ORF10 induced largely overlapping transcriptomes, ORF3a induced a distinct transcriptome, including the downregulation of numerous genes with critical roles in mitochondrial function and morphology. On the other hand, all four ORFs altered mitochondrial dynamics and function, but only ORF3a and ORF9c induced a marked alteration in mitochondrial cristae structure. Genome-Scale Metabolic Models identified both metabolic flux reprogramming features both shared across all accessory proteins and specific for each accessory protein. Notably, a downregulated amino acid metabolism was observed in ORF9b, ORF9c and ORF10, while an upregulated lipid metabolism was 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.
Keywords: ORF10; ORF3a; ORF9b; ORF9c; genome‐scale metabolic modeling; metabolomics; mitochondria; transcriptomics.
. 2024 Jul;96(7):e29752.
doi: 10.1002/jmv.29752. Metabolic and mitochondria alterations induced by SARS-CoV-2 accessory proteins ORF3a, ORF9b, ORF9c and ORF10
Blanca D López-Ayllón[SUP] 1 [/SUP], Silvia Marin[SUP] 2 3 4 [/SUP], Marco Fariñas Fernández[SUP] 2 5 [/SUP], Tránsito García-García[SUP] 6 7 [/SUP], Raúl Fernández-Rodríguez[SUP] 6 7 [/SUP], Ana de Lucas-Rius[SUP] 1 [/SUP], Natalia Redondo[SUP] 8 9 [/SUP], Laura Mendoza-García[SUP] 1 [/SUP], Carles Foguet[SUP] 10 [/SUP], Juozas Grigas[SUP] 11 12 [/SUP], Alba Calvet[SUP] 2 4 [/SUP], José Manuel Villalba[SUP] 13 [/SUP], María Josefa Rodríguez Gómez[SUP] 14 15 [/SUP], Diego Megías[SUP] 14 [/SUP], Biagio Mandracchia[SUP] 14 16 [/SUP], Daniel Luque[SUP] 14 17 18 [/SUP], Juan José Lozano[SUP] 3 [/SUP], Cristina Calvo[SUP] 19 [/SUP], Unai Merino Herrán[SUP] 1 [/SUP], Timothy M Thomson[SUP] 3 19 20 [/SUP], Juan J Garrido[SUP] 6 7 [/SUP], Marta Cascante[SUP] 2 3 4 [/SUP], María Montoya[SUP] 1 [/SUP]
Affiliations
- PMID: 38949191
- DOI: 10.1002/jmv.29752
Antiviral signaling, immune response and cell metabolism are dysregulated by SARS-CoV-2, the causative agent of 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 ORF9b, ORF9c and ORF10 induced largely overlapping transcriptomes, ORF3a induced a distinct transcriptome, including the downregulation of numerous genes with critical roles in mitochondrial function and morphology. On the other hand, all four ORFs altered mitochondrial dynamics and function, but only ORF3a and ORF9c induced a marked alteration in mitochondrial cristae structure. Genome-Scale Metabolic Models identified both metabolic flux reprogramming features both shared across all accessory proteins and specific for each accessory protein. Notably, a downregulated amino acid metabolism was observed in ORF9b, ORF9c and ORF10, while an upregulated lipid metabolism was 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.
Keywords: ORF10; ORF3a; ORF9b; ORF9c; genome‐scale metabolic modeling; metabolomics; mitochondria; transcriptomics.