title: Disruption of mitochondrial redox circuitry in oxidative stress.
abstract: The present review and commentary considers oxidative stress as a disruption of mitochondrial redox circuitry rather than an imbalance of oxidants and antioxidants. Mitochondria contain two types of redox circuits, high-flux pathways that are central to mechanisms for ATP production and low-flux pathways that utilize sulfur switches of proteins for metabolic regulation and cell signaling. The superoxide anion radical (hereafter termed "superoxide", O2*-), a well known free radical product of the high-flux mitochondrial electron transfer chain, provides a link between the high-flux and low-flux pathways. Disruption of electron flow and increased superoxide production occurs due to inhibition of electron transfer in the high-flux pathway, and this creates aberrant "short-circuit" pathways between otherwise non-interacting components. A hypothesis is presented that superoxide is not merely a byproduct of electron transfer but rather is generated by the mitochondrial respiratory apparatus to serve as a positive signal to coordinate energy metabolism. Electron mediators such as free Fe(3+) and redox-cycling agents, or potentially free radical scavenging agents, could therefore cause oxidative stress by disrupting this normal superoxide signal. Methods to map the regulatory redox circuitry involving sulfur switches (e.g., redox-western blotting of thioredoxin-2, redox proteomics) are briefly presented. Use of these approaches to identify sites of disruption in the mitochondrial redox circuitry can be expected to generate new strategies to prevent toxicity and, in particular, promote efforts to re-establish proper electron flow as a means to counteract pathologic effects of oxidative stress.
authors.affiliation: Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, Emory University, Atlanta, GA 30322, USA. dpjones@emory.edu <dpjones@emory.edu>
authors.forename: Dean P
authors.initials: DP
authors.lastname: Jones
mesh_terms: D000818:Animals; D004220:Disulfides / Q000378:metabolism; D004734:Energy Metabolism; D006801:Humans; D008928:Mitochondria / Q000502:physiology*; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D013438:Sulfhydryl Compounds / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism
chemical_list: D004220:Disulfides; D013438:Sulfhydryl Compounds; D013481:Superoxides