Generation of reactive oxygen species by the mitochondrial electron transport chain

TLDR

Reactive oxygen species produced by the mitochondrial electron transport chain are implicated in aging and neurodegenerative diseases, with prior studies pointing to the ubiquinone of complex III and an unknown component of complex I as major sites. The study demonstrates that succinate‑driven ROS production originates at the FMN site of complex I through reversed electron transfer, establishing the FMN group as the principal physiologically and pathologically relevant ROS‑generating site in mitochondria.

Abstract

Abstract Generation of reactive oxygen species (ROS) by the mitochondrial electron transport chain (ETC), which is composed of four multiprotein complexes named complex I–IV, is believed to be important in the aging process and in the pathogenesis of neurodegenerative diseases such as Parkinson's disease. Previous studies have identified the ubiquinone of complex III and an unknown component of complex I as the major sites of ROS generation. Here we show that the physiologically relevant ROS generation supported by the complex II substrate succinate occurs at the flavin mononucleotide group (FMN) of complex I through reversed electron transfer, not at the ubiquinone of complex III as commonly believed. Indirect evidence indicates that the unknown ROS‐generating site within complex I is also likely to be the FMN group. It is therefore suggested that the major physiologically and pathologically relevant ROS‐generating site in mitochondria is limited to the FMN group of complex I. These new insights clarify an elusive target for intervening mitochondrial ROS‐related processes or diseases.