Cellular effects of carbon monoxide

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DESCRIPTION (Applicant?s Abstract): This project is designed to investigate mechanisms by which low concentrations of CO could exert effects during hypoxia that would explain new preliminary data showing it mediates both apoptosis and cell proliferation or growth in vivo. Despite the presence of hypoxia, CO is associated with oxidative stress as shown by depletion of mitochondrial glutathione, and in the lung, increases in manganese superoxide dismutase (MnSOD) and heme oxygenase-1 (HO-1) expression. In addition, mitochondria from CO exposed animals are more sensitive ex vivo to ATP-facilitated permeability transition, which makes the cell more sensitive to mitochondrial initiation of apoptosis through cytochrome c release. These mitochondria are also susceptible to mtDNA degradation by NO, but not to mtDNA degradation by external oxidants such as t-butyl hydroperoxide. These data indicate that CO places a heavy oxidative/nitrosative burden on mitochondria. We propose that much of the oxidative burden is related to the respiratory chain because CO causes oxidation-reduction (redox) changes in the cytochrome b-c(l) region. We also hypothesize that increased mitochondrial leakage of H2O2 provides a redox signal to the cell. Therefore, we propose to pursue the mechanisms of CO-induced mitochondrial oxidant injury in Specific Aims 1 and 2, and investigate activation of mechanisms of signaling by CO that have redox response elements involved in apoptosis and/or cell proliferation in Specific Aims 3 and 4. Finally in Aim 5, we will investigate the possibility that HO-1, which produces CO endogenously, activates the same intracellular mechanisms associated with exogenous CO exposure. Thus, the project seeks to define a biological mechanism for the unique cellular responses to CO by testing the hypothesis that CO-related oxidative/nitrosative events directly alter mitochondrial permeability, redox and synthetic function and influence cell signaling and/or survival through these mechanisms.