Mitochondrial Reactive Oxygen Species Production in Excitable Cells: Modulators of Mitochondrial and Cell Function

Abstract

The mitochondrion is a major source of reactive oxygen species (ROS). Superoxide (O₂^•−) is generated under specific bioenergetic conditions at several sites within the electron-transport system; most is converted to H₂O₂ inside and outside the mitochondrial matrix by superoxide dismutases. H₂O₂ is a major chemical messenger that, in low amounts and with its products, physiologically modulates cell function. The redox state and ROS scavengers largely control the emission (generation scavenging) of O₂^•−. Cell ischemia, hypoxia, or toxins can result in excess O₂^•− production when the redox state is altered and the ROS scavenger systems are overwhelmed. Too much H₂O₂ can combine with Fe²⁺ complexes to form reactive ferryl species (e.g., Fe(IV) = O^•). In the presence of nitric oxide (NO^•), O₂^•− forms the reactant peroxynitrite (ONOO⁻), and ONOOH-induced nitrosylation of proteins, DNA, and lipids can modify their structure and function. An initial increase in ROS can cause an even greater increase in ROS and allow excess mitochondrial Ca²⁺ entry, both of which are factors that induce cell apoptosis and necrosis. Approaches to reduce excess O₂^•− emission include selectively boosting the antioxidant capacity, uncoupling of oxidative phosphorylation to reduce generation of O₂^•− by inducing proton leak, and reversibly inhibiting electron transport. Mitochondrial cation channels and exchangers function to maintain matrix homeostasis and likely play a role in modulating mitochondrial function, in part by regulating O₂^•− generation. Cell-signaling pathways induced physiologically by ROS include effects on thiol groups and disulfide linkages to modify posttranslationally protein structure to activate/inactivate specific kinase/phosphatase pathways. Hypoxia-inducible factors that stimulate a cascade of gene transcription may be mediated physiologically by ROS. Our knowledge of the role played by ROS and their scavenging systems in modulation of cell function and cell death has grown exponentially over the past few years, but we are still limited in how to apply this knowledge to develop its full therapeutic potential. Antioxid. Redox Signal. 11, 1373–1414.