Regulation of respiratory complex I assembly by FMN cofactor targeting

Curtabbi, Andrea ; Guarás, Adela ; Cabrera-Alarcón, José Luis ; Rivero, Maribel (Universidad de Zaragoza) ; Calvo, Enrique ; Rosa-Moreno, Marina ; Vázquez, Jesús ; Medina, Milagros (Universidad de Zaragoza) ; Enríquez, José Antonio

Resumen: 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.

Idioma: Inglés

DOI: 10.1016/j.redox.2023.103001

Año: 2024

Publicado en: Redox Biology 69 (2024), 103001 [15 pp.]
ISSN: 2213-2317

Factor impacto JCR: 11.9 (2024)

Categ. JCR: BIOCHEMISTRY & MOLECULAR BIOLOGY rank: 15 / 319 = 0.047 (2024) - Q1 - T1

Factor impacto SCIMAGO: 3.374 - Biochemistry (Q1) - Organic Chemistry (Q1) - Clinical Biochemistry (Q1)

Financiación: info:eu-repo/grantAgreement/ES/DGA/E35-23R
Financiación: info:eu-repo/grantAgreement/ES/MICINN/PID2021-127988OB-I00
Financiación: info:eu-repo/grantAgreement/ES/MICINN/PID2022-136369NB-I00
Financiación: info:eu-repo/grantAgreement/ES/MICINN/TED2021-131611B-I00

Tipo y forma: Article (Published version)

Área (Departamento): Área Bioquímica y Biolog.Mole. (Dpto. Bioq.Biolog.Mol. Celular)