Mitochondria Play Essential Roles in Intracellular Protection against Oxidative Stress-Which Molecules among the ROS Generated in the Mitochondria Can Escape the Mitochondria and Contribute to Signal Activation in Cytosol?

Questions about which reactive oxygen species (ROS) or reactive nitrogen species (RNS) can escape from the mitochondria and activate signals must be addressed. In this study, two parameters, the calculated dipole moment (debye, D) and permeability coefficient (Pm) (cm s-1), are listed for hydrogen peroxide (H2O2), hydroxyl radical (center dot OH), superoxide (O2 center dot-), hydroperoxyl radical (HO2 center dot), nitric oxide (center dot NO), nitrogen dioxide (center dot NO2), peroxynitrite (ONOO-), and peroxynitrous acid (ONOOH) in comparison to those for water (H2O). O2 center dot- is generated from the mitochondrial electron transport chain (ETC), and several other ROS and RNS can be generated subsequently. The candidates which pass through the mitochondrial membrane include ROS with a small number of dipoles, i.e., H2O2, HO2 center dot, ONOOH, center dot OH, and center dot NO. The results show that the dipole moment of center dot NO2 is 0.35 D, indicating permeability; however, center dot NO2 can be eliminated quickly. The dipole moments of center dot OH (1.67 D) and ONOOH (1.77 D) indicate that they might be permeable. This study also suggests that the mitochondria play a central role in protecting against further oxidative stress in cells. The amounts, the long half-life, the diffusion distance, the Pm, the one-electron reduction potential, the pKa, and the rate constants for the reaction with ascorbate and glutathione are listed for various ROS/RNS, center dot OH, singlet oxygen (1O2), H2O2, O2 center dot-, HO2 center dot, center dot NO, center dot NO2, ONOO-, and ONOOH, and compared with those for H2O and oxygen (O2). Molecules with negative electrical charges cannot directly diffuse through the phospholipid bilayer of the mitochondrial membranes. Short-lived molecules, such as center dot OH, would be difficult to contribute to intracellular signaling. Finally, HO2 center dot and ONOOH were selected as candidates for the ROS/RNS that pass through the mitochondrial membrane.