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...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2024-02-01
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| Series: | Redox Biology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231723004020 |
| _version_ | 1797376230241075200 |
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| author | Andrea Curtabbi Adela Guarás José Luis Cabrera-Alarcón Maribel Rivero Enrique Calvo Marina Rosa-Moreno Jesús Vázquez Milagros Medina José Antonio Enríquez |
| author_facet | Andrea Curtabbi Adela Guarás José Luis Cabrera-Alarcón Maribel Rivero Enrique Calvo Marina Rosa-Moreno Jesús Vázquez Milagros Medina José Antonio Enríquez |
| author_sort | Andrea Curtabbi |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-08T19:35:37Z |
| format | Article |
| id | doaj.art-a71adee731ca4f05938fc739793e0634 |
| institution | Directory Open Access Journal |
| issn | 2213-2317 |
| language | English |
| last_indexed | 2024-03-08T19:35:37Z |
| publishDate | 2024-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj.art-a71adee731ca4f05938fc739793e06342023-12-26T04:03:47ZengElsevierRedox Biology2213-23172024-02-0169103001Regulation of respiratory complex I assembly by FMN cofactor targetingAndrea Curtabbi0Adela Guarás1José Luis Cabrera-Alarcón2Maribel Rivero3Enrique Calvo4Marina Rosa-Moreno5Jesús Vázquez6Milagros Medina7José Antonio Enríquez8Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain; CIBER de Fragilidad y Envejecimiento Saludable (CIBERFES), Madrid, SpainCentro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, SpainCentro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain; CIBER de Fragilidad y Envejecimiento Saludable (CIBERFES), Madrid, SpainDepartamento de Bioquímica y Biología Molecular y Celular, Facultad de Ciencias, Universidad de Zaragoza, Zaragoza, Spain; Instituto de Biocomputación y Física de Sistemas Complejos (BIFI), Universidad de Zaragoza, Zaragoza, SpainCentro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain; CIBER de Enfermedades Cardiovasculares (CIBERCV), Madrid, SpainCentro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, SpainCentro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain; CIBER de Enfermedades Cardiovasculares (CIBERCV), Madrid, SpainDepartamento de Bioquímica y Biología Molecular y Celular, Facultad de Ciencias, Universidad de Zaragoza, Zaragoza, Spain; Instituto de Biocomputación y Física de Sistemas Complejos (BIFI), Universidad de Zaragoza, Zaragoza, SpainCentro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain; CIBER de Fragilidad y Envejecimiento Saludable (CIBERFES), Madrid, Spain; Corresponding author. Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain.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.http://www.sciencedirect.com/science/article/pii/S2213231723004020Respiratory complex IFMNOXPHOSDPI |
| spellingShingle | Andrea Curtabbi Adela Guarás José Luis Cabrera-Alarcón Maribel Rivero Enrique Calvo Marina Rosa-Moreno Jesús Vázquez Milagros Medina José Antonio Enríquez Regulation of respiratory complex I assembly by FMN cofactor targeting Redox Biology Respiratory complex I FMN OXPHOS DPI |
| title | 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_short | Regulation of respiratory complex I assembly by FMN cofactor targeting |
| title_sort | regulation of respiratory complex i assembly by fmn cofactor targeting |
| topic | Respiratory complex I FMN OXPHOS DPI |
| url | http://www.sciencedirect.com/science/article/pii/S2213231723004020 |
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