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

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

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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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

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network_acronym_str	ES
network_name_str	España
repository_id_str
spelling	Metabolic and mitochondria alterations induced by SARS-CoV-2 accessory proteins ORF3a, ORF9b, ORF9c and ORF10López-Ayllón, Blanca DMarin, SilviaFariñas Fernández, MarcoGarcía-García, TránsitoFernández-Rodríguez, Raúlde Lucas-Rius, AnaRedondo, NataliaMendoza-García, LauraFoguet, CarlesGrigas, JuozasCalvet, AlbaVillalba, José ManuelRodríguez, María JosefaMegías, DiegoMandracchia, BiagioLuque, DanielLozano, Juan JoséCalvo, CristinaMerino Herrán, UnaiThomson, Timothy MGarrido, Juan JCascante, MartaMontoya, MariaLópez-Ayllón, Blanca DMarin, SilviaFariñas Fernández, MarcoGarcía-García, TránsitoFernández-Rodríguez, Raúlde Lucas-Rius, AnaRedondo, NataliaMendoza-García, LauraFoguet, CarlesGrigas, JuozasCalvet, AlbaVillalba, José ManuelMegías, DiegoMandracchia, BiagioLuque, DanielLozano, Juan JoséCalvo, CristinaMerino Herrán, UnaiThomson, Timothy MGarrido, Juan JCascante, MartaMontoya, MaríaORF10ORF3aORF9bORF9cGenome‐scale metabolic modelingMetabolomicsMitochondriaTranscriptomicsA549 CellsCOVID-19HumansMitochondriaOpen Reading FramesSARS-CoV-2TranscriptomeViral ProteinsViral Regulatory and Accessory ProteinsViroporin ProteinsAntiviral 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.WileyUnión Europea. Comisión Europea. NextGenerationEUConsejo Superior de Investigaciones Científicas (España)Regional Government of Andalusia (España)Ministerio de Ciencia (España)Agència de Gestió d´Ajuts Universitaris i de Recerca (AGAUR)Institució Catalana de Recerca i Estudis AvançatsInstituto de Salud Carlos IIIAgencia Estatal de Investigación (España)20242024-11-0620242024-07-0120242024-07-01research articlehttp://purl.org/coar/resource_type/c_2df8fbb1VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfapplication/pdfapplication/vnd.openxmlformats-officedocument.spreadsheetml.sheetapplication/vnd.openxmlformats-officedocument.spreadsheetml.sheetapplication/vnd.openxmlformats-officedocument.wordprocessingml.documenthttps://hdl.handle.net/20.500.12105/25445reponame:Repisaludinstname:Instituto de Salud Carlos III (ISCIII)InglésengEC EU2020 2094ES COVID‐19‐117 Not availableES SGL2103015 Not availableES PID2021‐123399OB‐I00 Not availableES PI20CIII 00014open accesshttp://purl.org/coar/access_right/c_abf2Attribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:repisalud.isciii.es:20.500.12105/254452026-06-12T12:43:37Z
dc.title.none.fl_str_mv	Metabolic and mitochondria alterations induced by SARS-CoV-2 accessory proteins ORF3a, ORF9b, ORF9c and ORF10
title	Metabolic and mitochondria alterations induced by SARS-CoV-2 accessory proteins ORF3a, ORF9b, ORF9c and ORF10
spellingShingle	Metabolic and mitochondria alterations induced by SARS-CoV-2 accessory proteins ORF3a, ORF9b, ORF9c and ORF10 López-Ayllón, Blanca D ORF10 ORF3a ORF9b ORF9c Genome‐scale metabolic modeling Metabolomics Mitochondria Transcriptomics A549 Cells COVID-19 Humans Mitochondria Open Reading Frames SARS-CoV-2 Transcriptome Viral Proteins Viral Regulatory and Accessory Proteins Viroporin Proteins
title_short	Metabolic and mitochondria alterations induced by SARS-CoV-2 accessory proteins ORF3a, ORF9b, ORF9c and ORF10
title_full	Metabolic and mitochondria alterations induced by SARS-CoV-2 accessory proteins ORF3a, ORF9b, ORF9c and ORF10
title_fullStr	Metabolic and mitochondria alterations induced by SARS-CoV-2 accessory proteins ORF3a, ORF9b, ORF9c and ORF10
title_full_unstemmed	Metabolic and mitochondria alterations induced by SARS-CoV-2 accessory proteins ORF3a, ORF9b, ORF9c and ORF10
title_sort	Metabolic and mitochondria alterations induced by SARS-CoV-2 accessory proteins ORF3a, ORF9b, ORF9c and ORF10
dc.creator.none.fl_str_mv	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 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 Megías, Diego Mandracchia, Biagio Luque, Daniel Lozano, Juan José Calvo, Cristina Merino Herrán, Unai Thomson, Timothy M Garrido, Juan J Cascante, Marta Montoya, María
author	López-Ayllón, Blanca D
author_facet	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
author_role	author
author2	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
author2_role	author author author author author author author author author author author author author author author author author author author author author author author
dc.contributor.none.fl_str_mv	Unión Europea. Comisión Europea. NextGenerationEU Consejo Superior de Investigaciones Científicas (España) Regional Government of Andalusia (España) Ministerio de Ciencia (España) Agència de Gestió d´Ajuts Universitaris i de Recerca (AGAUR) Institució Catalana de Recerca i Estudis Avançats Instituto de Salud Carlos III Agencia Estatal de Investigación (España)
dc.subject.none.fl_str_mv	ORF10 ORF3a ORF9b ORF9c Genome‐scale metabolic modeling Metabolomics Mitochondria Transcriptomics A549 Cells COVID-19 Humans Mitochondria Open Reading Frames SARS-CoV-2 Transcriptome Viral Proteins Viral Regulatory and Accessory Proteins Viroporin Proteins
topic	ORF10 ORF3a ORF9b ORF9c Genome‐scale metabolic modeling Metabolomics Mitochondria Transcriptomics A549 Cells COVID-19 Humans Mitochondria Open Reading Frames SARS-CoV-2 Transcriptome Viral Proteins Viral Regulatory and Accessory Proteins Viroporin Proteins
description	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.
publishDate	2024
dc.date.none.fl_str_mv	2024 2024-11-06 2024 2024-07-01 2024 2024-07-01
dc.type.none.fl_str_mv	research article http://purl.org/coar/resource_type/c_2df8fbb1 VoR http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv	info:eu-repo/semantics/article
format	article
dc.identifier.none.fl_str_mv	https://hdl.handle.net/20.500.12105/25445
url	https://hdl.handle.net/20.500.12105/25445
dc.language.none.fl_str_mv	Inglés eng
language_invalid_str_mv	Inglés
language	eng
dc.relation.none.fl_str_mv	EC EU2020 2094 ES COVID‐19‐117 Not available ES SGL2103015 Not available ES PID2021‐123399OB‐I00 Not available ES PI20CIII 00014
dc.rights.none.fl_str_mv	open access http://purl.org/coar/access_right/c_abf2 Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.rights.openaire.fl_str_mv	info:eu-repo/semantics/openAccess
rights_invalid_str_mv	open access http://purl.org/coar/access_right/c_abf2 Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv	openAccess
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dc.publisher.none.fl_str_mv	Wiley
publisher.none.fl_str_mv	Wiley
dc.source.none.fl_str_mv	reponame:Repisalud instname:Instituto de Salud Carlos III (ISCIII)
instname_str	Instituto de Salud Carlos III (ISCIII)
reponame_str	Repisalud
collection	Repisalud
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score	15,81155

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

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