doi:10.1016/j.redox.2023.103001engCurtabbi, AndreaGuarás, AdelaCabrera-Alarcón, José LuisRivero, MaribelCalvo, EnriqueRosa-Moreno, MarinaVázquez, JesúsMedina, MilagrosEnríquez, José AntonioRegulation of respiratory complex I assembly by FMN cofactor targetingART-2024-137761Respiratory 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.2024http://zaguan.unizar.es/record/13279010.1016/j.redox.2023.103001http://zaguan.unizar.es/record/132790oai:zaguan.unizar.es:132790info: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-I00Redox Biology 69 (2024), 103001 [15 pp.]by-nc-ndhttps://creativecommons.org/licenses/by-nc-nd/4.0/deed.esinfo:eu-repo/semantics/openAccess