Determining the origins of superoxide and hydrogen peroxide in the mammalian NADH:ubiquinone oxidoreductase. Free Radic Biol Med 2014 Dec;77:121-9
Date
09/23/2014Pubmed ID
25236739Pubmed Central ID
PMC4258523DOI
10.1016/j.freeradbiomed.2014.08.023Scopus ID
2-s2.0-84908306065 (requires institutional sign-in at Scopus site) 30 CitationsAbstract
NADH:ubiquinone oxidoreductase (complex I) is a proton pump in the electron transport chain that can produce a significant amounts of superoxide and hydrogen peroxide. While the flavin mononucleotide (FMN) is the putative site for hydrogen peroxide generation, sites responsible for superoxide are less certain. Here, data on complex I kinetics and ROS generation are analyzed using a computational model to determine the sites responsible for superoxide. The analysis includes all the major redox centers: the FMN, iron-sulfur cluster N2, and semiquinone. Analysis reveals that the fully reduced FMN and semiquinone are the primary sources of superoxide, and the iron-sulfur cluster N2 produces none. The FMN radical only produces ROS when the quinone reductase site is blocked. Model simulations reveal that ROS generation is maximized during reverse electron transport with both the FMN and the semiquinone producing similar amounts of superoxide. In addition, the model successfully predicts the increase in ROS generation when the membrane potential is high and matrix pH is alkaline. Of the total ROS produced by complex I, the majority originates from the FMN.
Author List
Bazil JN, Pannala VR, Dash RK, Beard DAAuthor
Ranjan K. Dash PhD Professor in the Biomedical Engineering department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsComputer Simulation
Electron Transport Complex I
Humans
Hydrogen Peroxide
Hydrogen-Ion Concentration
Kinetics
NAD
Oxidation-Reduction
Superoxides
