📒 Bazil 2016

Catalytic Coupling of Oxidative Phosphorylation, ATP Demand, and Reactive Oxygen Species Generation1


Based on the two previous papers.23


  • the concentration of cytoplasmic Pi is thought to be the most important feedback signal controlling oxidative phosphorylation
  • alternative hypothesis: open-loop stimulation by calcium => attempts to demonstrate these stimulatory effects within the physiological range of calcium concentrations, temperature, ionic strength, and substrate concentrations, have failed
  • Elevated ROS levels from complex I caused by matrix alkalization after mitochondrial KATP channel opening contributes to cardioprotection against ischemia/reperfusion injury. But the existence of the KATP channel is still debated
  • Extrapolating ROS production rates measured in vitro to expected rates in vivo must be done with caution
  • As it is currently extremely difficult to accurately measure ROS production in vivo, a mathematical model is required
  • Our recent work identifying and analyzing thermodynamically constrained models describing the catalytic mechanisms of respiratory complexes Iand III
  • predicts that an increase in the quinone pool (Q pool) redox state is responsible for the apparent activation of complex III by inorganic phosphate

Materials and Methods

  • The model descriptors for NADH production, complexes I, III, and IV were updated from the 2005 Beard model to capture the substrate/product and hydrogen peroxide/superoxide production kinetics

Results and Discussion

  • orange: with succinate accumulation. blue: without succinate accumulation
  • For the ischemic period, the O2 concentration was set to 1 nM to reflect the hypoxic conditions during ischemia. For the reperfusion period, the O2 concentration was set back to the baseline value.
  • For the I/R Simulation 2 conditions, RET is the dominant source of ROS and leads to a 10-fold higher ROS production rate compared to forward electron transport
  • This conclusion is strongly corroborated by Chouchani et al. , who demonstrate that elevated ROS production during reperfusion after ischemia is due to accumulation of mitochondrial succinate


  • an oxidative-phosphorylation model that is capable of simulating ROS dynamics
  • updated complexes I, III, and IV, and ANT


  1. Bazil JN, Beard DA, Vinnakota KC. Catalytic Coupling of Oxidative Phosphorylation, ATP Demand, and Reactive Oxygen Species Generation. Biophys J. 2016;110(4):962-71. PMC4776027 ↩︎

  2. Bazil JN, Pannala VR, Dash RK, Beard DA. Determining the origins of superoxide and hydrogen peroxide in the mammalian NADH:ubiquinone oxidoreductase. Free Radic Biol Med. 2014;77:121-9. PMC4258523 ↩︎

  3. Bazil JN, Vinnakota KC, Wu F, Beard DA. Analysis of the kinetics and bistability of ubiquinol:cytochrome c oxidoreductase. Biophys J. 2013;105(2):343-55. PMC3714890 ↩︎