Figure 5.

Simulation of a proton spike and schematic model for mitoflash genesis. (A) Matrix proton spike induced by proton uncaging. In this simulation, uncaging at time = 0 ns elicited a sudden drop in pH (from 8 to 4) or a surge of protons (upper inset) and a steady bulk matrix pH change of 0.02 unit (lower inset). The mean lifetime of the uncaged protons was 1.42 ns and the mean distance of diffusion was 2.06 nm. (B) A stochastic, flickering opening of the mPTP results in water and ionic fluxes to strain and depolarize the IMM. The mechanical strain causes dislocation of ETC molecules and disruption of the normal electron path, and thus greatly increases electron leakage to oxygen, resulting in a burst of superoxide formation. Meanwhile, depolarization accelerates electron transfer from the donor pool to ETC acceptors (e.g., from NADH to complex I, and from FADH₂ to complex II) and shifts the redox potential toward oxidation. Accelerated ETC activity, driven dually by depolarization and oxygen deprivation of ETC electrons, stimulates coupled proton pumping across the IMM, giving rise to matrix alkalinization. Among others, nanodomain protons at the IMM may directly bind to a putative proton-binding site and thereby trigger transient opening of the mPTP to initiate a cascade of changes in a mitoflash. To see this figure in color, go online.