Simulating Free Radical Production from Complex I

Abstract

Complex I is a respiratory pump (NADH:quinone oxidoreductase) in the electron transport chain of mitochondria that can produce a significant amount of reactive oxygen species (ROS) in the form of superoxide and hydrogen peroxide. Hydrogen peroxide is formed at the flavin mononucleotide (FMN), but the location of superoxide production is less certain. A computer model fit to kinetic data is used to determine the location and rates of ROS production. The model includes the major redox centers in the complex: the FMN, iron-sulfur cluster N2, and semiquinone. The analysis identifies that the fully reduced FMN and semiquinone are the major sources of superoxide with little to no production from the iron-sulfur cluster N2. Also, the FMN radical only produces superoxide when turnover at the quinone-reductase site is blocked. When electron flow through the complex is reversed, ROS production is maximized with the FMN and semiquinone producing similar amounts. Moreover, high membrane potentials and alkaline matrix pH stimulate ROS production. Of all the ROS produced, the majority originates from the FMN. The Complex I model is integrated into a larger model of the respiratory chain that includes ROS production from Complex III, and the relative rates of ROS production from each complex is determined under a variety of simulated conditions.