Deterministic Chaos and Mitochondrial Synthesis of Reactive Oxygen Species

We tested the Lotan hypothesis that two potent anticancer retinoids, all-trans retinoic acid (atRA) and N-(4-hydroxyphenyl) retinamide (4-HPR) interfere with mitochondrial electron transport enhancing synthesis of reactive oxygen species (ROS). Mitochondria isolated from normal rat liver and three human uroepithelial cell lines T24, TCC-Sup and RT4 were used in this study. Membrane potential (Δψ) was measured simultaneously with oxygen consumption when mitochondria were incubated with 10 µM atRA or 5µM 4-HPR. Subsequently, synthesis of ROS was monitored by spin trap electroparamagnetic resonance (EPR) and spectrofluorescence (SF). Uncoupling of mitochondrial respiration by atRA or 4-HPR with succinate as oxidizable substrate was observed (i.e. decrease in both ADP/O and respiratory control (RC) ratio). Thus, the hypothesis must be rejected. Mathematical model indicates that chaotic oscillations of the concentrations of superoxide anion observed in the experiment are caused by some autocatalytic interactions between free radicals and oxygen molecules. Those interactions lead to the emergence of teleological, complex, fractal dynamics in both mitochondrial electron transport chain and ATP synthesis. From the perspective of deterministic chaotic dynamics, electron transport is not a simplistic phenomenon, nor is ROS synthesis its by-process. The observed uncoupling leads to the ATP deficit and may protect tissues against damage, e.g., caused by radiotherapy.