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 (H 2 O 2 ), hydroxyl radical (•OH), superoxide (O 2 •- ), hydroperoxyl radical (HO 2 •), nitric oxide (•NO), nitrogen dioxide (•NO 2 ), peroxynitrite (ONOO - ), and peroxynitrous acid (ONOOH) in comparison to those for water (H 2 O). O 2 •- 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., H 2 O 2 , HO 2 •, ONOOH, •OH, and •NO. The results show that the dipole moment of •NO 2 is 0.35 D, indicating permeability; however, •NO 2 can be eliminated quickly. The dipole moments of •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 p K a , and the rate constants for the reaction with ascorbate and glutathione are listed for various ROS/RNS, •OH, singlet oxygen ( 1 O 2 ), H 2 O 2 , O 2 •- , HO 2 •, •NO, •NO 2 , ONOO - , and ONOOH, and compared with those for H 2 O and oxygen (O 2 ). Molecules with negative electrical charges cannot directly diffuse through the phospholipid bilayer of the mitochondrial membranes. Short-lived molecules, such as •OH, would be difficult to contribute to intracellular signaling. Finally, HO 2 • and ONOOH were selected as candidates for the ROS/RNS that pass through the mitochondrial membrane.