Controlled Release of Reactive Oxygen Species for Mitochondria and Cellular Redox Signaling Pathways

Another possible role of mitochondrial involvement in atherosclerosis is the release of reactive oxygen species in a highly controlled process, at least under nonpatho-logic conditions, and its linkage with a well-orchestrated signal transduction system, the "redox cell signaling" system. In support of this concept, the release of reactive oxygen species from mitochondria appears regulated by specific mechanisms. Superoxide formation by complex I in the respiratory chain is influenced by a thiol switching mechanism. The glutaredoxin system controls the redox couples of a 70-kDa subunit of complex I. S-glutathionylation of the protein increases superoxide release.83 Another mechanism involves uncoupling protein 2. This protein reduces the proton potential across the mitochondrial membranes. It also reduces the formation of superoxide anion and oxidative damage with increases in its expression.84,85 This effect is dependent on the particular isoform of UCP, as UCP1 has the opposite effect. These observations suggest a system of controls for the release of reactive oxygen species, which requires further exploration. Efforts have just begun in this area and confirmation of these mechanisms is necessary.

Regarding possible ROS signaling mechanisms within mitochondria, superoxide anions can bind to aconitase, an iron-sulfur protein in the respiratory chain, and cause the release of iron.86 The released iron can cause lipid peroxidation with the formation of oxidized (electrophilic) lipids. The electrophilic lipids are bioac-tive. They can react with protein thiols and induce a range of signals. Another possible pathway involves peroxynitrite, which is formed from nitric oxide and superoxide and has been linked with signal transduction systems.87 It is also a potent oxidant and can induce lipid peroxidation and formation of bioactive lipids.

Hydrogen peroxide may act in two additional pathways, superoxide dismutase produces hydrogen peroxide from superoxide anion and it is ready diffusible through membranes. It can interact with cytosolic redox sensitive proteins and pathways.88 Hydrogen peroxide also can react with peroxidases, such as myeloperoxidase, and reactive nitrogen species with the production of nitrated proteins.89

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