Contents

📒 Bazil 2016

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

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Based on the two previous papers.23

Introduction

  • 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

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4776027/bin/gr1.jpg

  • 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

https://els-jbs-prod-cdn.literatumonline.com/cms/attachment/fd0bb97e-3d16-485c-b0ce-320f7116785a/gr2_lrg.jpg https://els-jbs-prod-cdn.literatumonline.com/cms/attachment/89b6667c-8826-40e3-90ea-26d54f8b3608/gr3_lrg.jpg https://els-jbs-prod-cdn.literatumonline.com/cms/attachment/59489da7-676a-49b4-9471-eaa53e18705c/gr4_lrg.jpg https://els-jbs-prod-cdn.literatumonline.com/cms/attachment/e8d29fef-afbf-4e54-a0ea-406658893caf/gr5_lrg.jpg https://els-jbs-prod-cdn.literatumonline.com/cms/attachment/92ce0532-ea49-4206-8d6c-33552ca5ce8c/gr6_lrg.jpg

  • 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

Conclusion

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

References


  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 ↩︎