FIGURE 18.

Two-ROS thresholds scheme for the induction of the mPTP. Resting state (shown by a pink ball) is a state with a stable closed mPTP. After depletion of a redox buffer, the pore may undergo a transition to a metastable flickering state (I) (shown by yellow color). The flickering mode of the pore is accompanied by a small release of ROS from mitochondria, and when low it serves a physiological housekeeping purposes as a release valve and when higher it is enough to precondition the system for better output after the following, more extensive oxidative challenge (180). If the oxidative stress is severe, the phase I is changed by a state II (shown by red) characterized by a stable open mPTP accompanied by a ROS burst. The pathological ROS burst results in a programmed elimination of unwanted organelles or cells. The critical height of the ROS threshold is determined by a balance between ROS production and quenching within mitochondria. It can be raised by protective signaling [through preconditioning (218), cyclosporin A (180, 218), sanglofehrin (89), acidosis (47), cyclophilin D acetylation or its knockout (26, 34, 313, 387)] shown by a green dotted line. Low redox buffering (491), low SIRT3 activity (387), hexokinase II detachment from mitochondria (86), as well as high age (216, 487) drive the threshold II down (shown by a brown dotted line). Note that one of the most important elements of the scheme is that the long occupancy in state I hardens the onset of the state II.