Oxidation-sensitive residue, including its apparent pKa and its exposure to the
Oxidation-sensitive residue, including its apparent pKa and its exposure to the intracellular milieu, contributes to the ease with which it PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/27735993 is modified by ROS [80]. It is these properties that can impart specificity in the oxidative modification of proteins. Mitochondrial ROS arise from a one-electron reduction of molecular oxygen by electron carriers and other matrix enzymes to produce the superoxide anion. This charged species is rapidly converted to H2O2 peroxide, which, unlike its progenitor superoxide, is capable of diffusing from mitochondria to the cytosol where it may subsequently alter the activities of proteins that include transcription factors and components of signaling pathways. Intracellular H2O2 concentrations are capable offluctuating on a rapid timescale in response to internal and external cues. In addition, this particular species is relatively inert to reaction with macromolecules, a property that enables its diffusion in the cytosol and is consistent with its proposed actions as a signaling molecule [80]. ROS have been shown to participate in directing the cellular response under pathological conditions, including hypoxia, inflammatory signals, starvation and ischemia reperfusion [79,81]. In the context of animal aging, a trend towards a more oxidative environment with increasing age (for example, Cocheme et al., [82]) may impact the activities of a suite of signaling pathways involved in regulating lifespan and in the development of age-related disease. Beyond a function in signaling under stress conditions, a Necrostatin-1 web putative role for ROS in the proliferation and differentiation of animal cells has been outlined on the basis of observations made following the manipulation of ROS levels. Growth factors, such as IGF-1, VEGF and EGF, stimulate ROS production that inactivates tyrosine phosphatases, and in turn permits the propagation of signaling pathways favoring growth and division (reviewed in [83]). In contrast, overexpression of catalase or glutathione peroxidase (two enzymes that detoxify H2O2) inhibits H2O2 and serum-stimulated proliferation in endothelial cells (Ruiz-Gines et al. [84]; Faucher et al., [85]). In vivo, overexpression of a mitochondria-targeted catalase in mice reduces the incidence of breast cancer tumor formation in these animals, data that provide tentative support of a potential role for mitochondrial H2O2 production as a mitogenic signal in vivo [86]. While these data could be used to build the argument that a reduction in mitochondrial ROS production reduces cancer in older populations, it is important to note that overexpression of antioxidant enzymes that reduce intracellular ROS levels are not generally associated with increased longevity, and that the roles of mitochondrial ROS are complex. However, the effects of H2O2 on the cell cycle are not completely straightforward, as altered intracellular H2O2 concentrations have also been reported to slow cell proliferation. For example, manipulation of endogenous mitochondrial H2O2 production via alterations in MnSOD levels has been shown to promote entry into quiescence [87], and to slow proliferation in a number of cancerous cell lines (for example, [88-90]). In human glioma cells the concomitant overexpression of MnSOD and GPx abolishes the growth inhibitory effects that are associated with MnSOD overexpression alone, suggesting that in this cell type the MnSOD-stimulated increase in H2O2 concentrations underlies changes in proliferation [91]. Thu.