Curtabbi 2023 Redox Biol

Curtabbi A, Guarás A, Cabrera-Alarcón JL, Rivero M, Calvo E, Rosa-Moreno M, Vázquez J, Medina M, Enríquez JA (2023) Regulation of respiratory complex I assembly by FMN cofactor targeting. https://doi.org/10.1016/j.redox.2023.103001

» Redox Biol [Epub ahead of print]. PMID: 38145589 Open Access

Curtabbi Andrea, Guaras Adela, Cabrera-Alarcon Jose Luis, Rivero Maribel, Calvo Enrique, Rosa-Moreno Marina, Vazquez Jesus, Medina Milagros, Enriquez Jose Antonio (2023) Redox Biol

Abstract: 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. • Keywords: DPI, FMN, OXPHOS, Respiratory complex I • Bioblast editor: Plangger M • O2k-Network Lab: ES Madrid Enriquez JA

Labels: MiParea: Respiration, Genetic knockout;overexpression, Pharmacology;toxicology 

Organism: Mouse  Tissue;cell: Kidney, Fibroblast  Preparation: Permeabilized cells, Isolated mitochondria  Enzyme: Complex I 

Coupling state: OXPHOS  Pathway: N, S, CIV  HRR: Oxygraph-2k 

2024-01