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

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...

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Detalles Bibliográficos
Autores: López-Ayllón, Blanca D, Marin, Silvia, Fariñas Fernández, Marco, García-García, Tránsito, Fernández-Rodríguez, Raúl, de Lucas-Rius, Ana, Redondo, Natalia, Mendoza-García, Laura, Foguet, Carles, Grigas, Juozas, Calvet, Alba, Villalba, José Manuel, Rodríguez, María Josefa, Megías, Diego, Mandracchia, Biagio, Luque, Daniel, Lozano, Juan José, Calvo, Cristina, Merino Herrán, Unai, Thomson, Timothy M, Garrido, Juan J, Cascante, Marta, Montoya, Maria, Montoya, María
Tipo de recurso: artículo
Fecha de publicación:2024
País:España
Institución:Instituto de Salud Carlos III (ISCIII)
Repositorio:Repisalud
Idioma:inglés
OAI Identifier:oai:repisalud.isciii.es:20.500.12105/25445
Acceso en línea:https://hdl.handle.net/20.500.12105/25445
Access Level:acceso abierto
Palabra clave:ORF10
ORF3a
ORF9b
ORF9c
Genome‐scale metabolic modeling
Metabolomics
Mitochondria
Transcriptomics
A549 Cells
COVID-19
Humans
Open Reading Frames
SARS-CoV-2
Transcriptome
Viral Proteins
Viral Regulatory and Accessory Proteins
Viroporin Proteins
Descripción
Sumario: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.

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