The ins and outs of the flavin mononucleotide cofactor of respiratory complex I

The flavin mononucleotide (FMN) cofactor of respiratory complex I occupies a key position in the electron transport chain. Here, the electrons coming from NADH start the sequence of oxidoreduction reactions, which drives the generation of the proton-motive force necessary for ATP synthesis. The overall architecture and the general catalytic proprieties of the FMN site are mostly well established. However, several aspects regarding the complex I flavin cofactor are still unknown. For example, the flavin binding to the N-module, the NADH-oxidizing portion of complex I, lacks a molecular description. The dissociation of FMN from the enzyme is beginning to emerge as an important regulatory mechanism of complex I activity and ROS production. Finally, how mitochondria import and metabolize FMN is still uncertain. This review summarizes the current knowledge on complex I flavin cofactor and discusses the open questions for future research.