Mechanisms of cytoplasmic-mitochondrial redox balance and interaction with mitochondrial energetics: A computational study

MIGUEL A. AON; JACKELYN M. KEMBRO; BRIAN OROURKE; NAZARENO PAOLOCCI; SONIA CORTASSA

Woods Hole, Massachusetts

Encuentro; Sixty-fifth annual meeting of the Society of General Physiologists: Mitochondrial Physiology and Mediciney; 2011

the society of general physiologists

The Redox-Optimized ROS Balance (R-ORB)hypothesis postulates that the redox environment determines reactive oxygen species (ROS) levels in mitochondria and cells. Maximal rates of respiration and ATP synthesis and minimal ROS levels occur at intermediate redox environments. Overflow of ROShappens: (i) at more reduced redox environments when mitochondrial ROS production exceeds scavenging, and (ii) under more oxidizing conditions when antioxidant defenses are compromised. Herein we study the role of the antioxidant defenses in determining mitochondrial redox balance dynamics under different energetic conditions. The computational model utilized accounts for the production of ROS in the respiratory chain and ROS scavenging, in the mitochondrial matrix and extramitochondrial compartments. This version of the mitochondrial model includes glutathione- and thioredoxin-scavenging systems, and was built upon the mitochondrial energetics one that comprises energy metabolism and protons, Ca2+, Na+ and Pi dynamics (Wei et al. 2011. Biophys. J.). The stability analysis of the model as a function of cytoplasmic ADP (ADPi) exhibits the typical transition between respiratory states 4 to 3. With the exception of NADH, ROS species and other redox variables did not change significantly with ADPi. The model displays oscillations in membrane potential (m) and redox intermediates under state 4 but not state 3 respiration. The dynamics in the oscillatory regime, driven by excess superoxide (O2 .−) production or insufficient scavenging, involves large amplitude cycles of m, NADH, cytoplasmic O2.−, and H2O2 in both compartments. Oscillatory periods ranging from 14 s to 5 min, and an inverse correlation between the amplitude and the period of the oscillations were found. Model simulation results obtained are in agreement with the prediction by the R-ORB hypothesis under oxidizing redox environments. In addition, it shows that mitochondrial oscillatory dynamics tend to happen under more energized and reduced conditions, when respiratory rates are lower.