Regulation of respiratory complex I assembly by FMN cofactor targeting

Respiratory complex I plays a crucial role in the mitochondrial electron transport chain and shows promise as a therapeutic target for various human diseases. While most studies focus on inhibiting complex I at the Q-site, little is known about inhibitors targeting other sites within the complex. In...

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Autores: Curtabbi, Andrea, Guarás, Adela, Cabrera-Alarcón, José Luis, Rivero, Maribel, Calvo, Enrique, Rosa-Moreno, Marina, Vázquez, Jesús, Medina, Milagros, Enríquez, José Antonio
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2024
País:España
Institución:Universidad de Zaragoza
Repositorio:Zaguán. Repositorio Digital de la Universidad de Zaragoza
OAI Identifier:oai:zaguan.unizar.es:132790
Acceso en línea:http://zaguan.unizar.es/record/132790
Access Level:acceso abierto
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spelling Regulation of respiratory complex I assembly by FMN cofactor targetingCurtabbi, AndreaGuarás, AdelaCabrera-Alarcón, José LuisRivero, MaribelCalvo, EnriqueRosa-Moreno, MarinaVázquez, JesúsMedina, MilagrosEnríquez, José AntonioRespiratory complex I plays a crucial role in the mitochondrial electron transport chain and shows promise as a therapeutic target for various human diseases. While most studies focus on inhibiting complex I at the Q-site, little is known about inhibitors targeting other sites within the complex. In this study, we demonstrate that diphenyleneiodonium (DPI), a N-site inhibitor, uniquely affects the stability of complex I by reacting with its flavin cofactor FMN. Treatment with DPI blocks the final stage of complex I assembly, leading to the complete and reversible degradation of complex I in different cellular models. Growing cells in medium lacking the FMN precursor riboflavin or knocking out the mitochondrial flavin carrier gene SLC25A32 results in a similar complex I degradation. Overall, our findings establish a direct connection between mitochondrial flavin homeostasis and complex I stability and assembly, paving the way for novel pharmacological strategies to regulate respiratory complex I.2024info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttp://zaguan.unizar.es/record/132790reponame:Zaguán. Repositorio Digital de la Universidad de Zaragozainstname:Universidad de ZaragozaInglésinfo:eu-repo/grantAgreement/ES/DGA/E35-23Rinfo:eu-repo/grantAgreement/ES/MICINN/PID2021-127988OB-I00info:eu-repo/grantAgreement/ES/MICINN/PID2022-136369NB-I00info:eu-repo/grantAgreement/ES/MICINN/TED2021-131611B-I00info:eu-repo/semantics/openAccessoai:zaguan.unizar.es:1327902026-05-29T13:59:51Z
dc.title.none.fl_str_mv Regulation of respiratory complex I assembly by FMN cofactor targeting
title Regulation of respiratory complex I assembly by FMN cofactor targeting
spellingShingle Regulation of respiratory complex I assembly by FMN cofactor targeting
Curtabbi, Andrea
title_short Regulation of respiratory complex I assembly by FMN cofactor targeting
title_full Regulation of respiratory complex I assembly by FMN cofactor targeting
title_fullStr Regulation of respiratory complex I assembly by FMN cofactor targeting
title_full_unstemmed Regulation of respiratory complex I assembly by FMN cofactor targeting
title_sort Regulation of respiratory complex I assembly by FMN cofactor targeting
dc.creator.none.fl_str_mv Curtabbi, Andrea
Guarás, Adela
Cabrera-Alarcón, José Luis
Rivero, Maribel
Calvo, Enrique
Rosa-Moreno, Marina
Vázquez, Jesús
Medina, Milagros
Enríquez, José Antonio
author Curtabbi, Andrea
author_facet Curtabbi, Andrea
Guarás, Adela
Cabrera-Alarcón, José Luis
Rivero, Maribel
Calvo, Enrique
Rosa-Moreno, Marina
Vázquez, Jesús
Medina, Milagros
Enríquez, José Antonio
author_role author
author2 Guarás, Adela
Cabrera-Alarcón, José Luis
Rivero, Maribel
Calvo, Enrique
Rosa-Moreno, Marina
Vázquez, Jesús
Medina, Milagros
Enríquez, José Antonio
author2_role author
author
author
author
author
author
author
author
description Respiratory complex I plays a crucial role in the mitochondrial electron transport chain and shows promise as a therapeutic target for various human diseases. While most studies focus on inhibiting complex I at the Q-site, little is known about inhibitors targeting other sites within the complex. In this study, we demonstrate that diphenyleneiodonium (DPI), a N-site inhibitor, uniquely affects the stability of complex I by reacting with its flavin cofactor FMN. Treatment with DPI blocks the final stage of complex I assembly, leading to the complete and reversible degradation of complex I in different cellular models. Growing cells in medium lacking the FMN precursor riboflavin or knocking out the mitochondrial flavin carrier gene SLC25A32 results in a similar complex I degradation. Overall, our findings establish a direct connection between mitochondrial flavin homeostasis and complex I stability and assembly, paving the way for novel pharmacological strategies to regulate respiratory complex I.
publishDate 2024
dc.date.none.fl_str_mv 2024
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://zaguan.unizar.es/record/132790
url http://zaguan.unizar.es/record/132790
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv info:eu-repo/grantAgreement/ES/DGA/E35-23R
info:eu-repo/grantAgreement/ES/MICINN/PID2021-127988OB-I00
info:eu-repo/grantAgreement/ES/MICINN/PID2022-136369NB-I00
info:eu-repo/grantAgreement/ES/MICINN/TED2021-131611B-I00
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv
publisher.none.fl_str_mv
dc.source.none.fl_str_mv reponame:Zaguán. Repositorio Digital de la Universidad de Zaragoza
instname:Universidad de Zaragoza
instname_str Universidad de Zaragoza
reponame_str Zaguán. Repositorio Digital de la Universidad de Zaragoza
collection Zaguán. Repositorio Digital de la Universidad de Zaragoza
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15.300719

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