Using a Superoxide Dismutase Mimetic to Mitigate Age-Associated, Radiation-Induced Cardiopulmonary Damage: Investigating the Role of Nitro-Oxidative Signaling and Mitochondrial Metabolism

PROJECT SUMMARY/ABSTRACT. An aging population faces unique health challenges, including increased susceptibility to ionizing radiation (IR) toxicities due to oxidative and nitrative metabolic changes. Elderly individuals are particularly vulnerable to IR-induced cardiopulmonary toxicities due to age-related physiological changes that impair tissue repair and regeneration. Age-associated decline in metabolic efficiency generates increased reactive oxygen species [i.e., superoxide (O2•−)]. IR exposure may also induce bursts of O2•− and nitrative species [i.e., nitric oxide (NO)]. Excess O2•− can combine with NO to form peroxynitrite (ONOO-) that can damage proteins, lipids, and DNA leading to inflammation and fibrosis. O2•− can disrupt the mitochondrial electron transport chain (ETC) complexes I and III while ONOO- inhibits mitochondrial ETC complex II. Inhibition of the ETC complexes leads to increased residence time of electrons at specific sites in the ETC, disrupting ETC stoichiometry and further increasing O2•− formation, resulting in a state of persistent oxidative stress and subsequent cardiopulmonary damage. This proposal investigates the age-associated impact of nitro-oxidative metabolism on mitochondrial ETC complex efficiency and cardiopulmonary physiology. Utilizing genetically modified mice and an upper body irradiation (UBI) model, we will elucidate the impact of nitric oxide synthase 1 (Nos1) disruption and assess the efficacy of a superoxide dismutase mimetic (Rucosopasem) in ameliorating age-associated cardiopulmonary effects induced by IR. We hypothesize that age-associated, IR-induced disruptions in the assembly of mitochondrial complexes result in stochiometric mismatches and alterations in the generation of O2•− and ONOO- leading to differential IR-induced cardiac and pulmonary phenotypes based on age. Aim 1 will define the age- associated effects of UBI on the stoichiometry of the ETC complexes in WT and Nos1+/- murine models and the effects on cardiopulmonary pathophysiology. Aim 2 will determine the efficacy of a clinically relevant superoxide dismutase (SOD) mimetic, Rucusopasem, to target the alterations in mitochondrial ETC stoichiometry, reduce ONOO- and O2•− formation, and mitigate the age-related IR-induced effects on the cardiopulmonary system. Completing these studies may unveil age-associated differences in nitro-oxidative metabolism and mitochondrial dysfunction, potentially identifying targets to prevent or reduce IR-induced cardiopulmonary toxicities. Moreover, if treatment with a superoxide dismutase mimetic restores ETC complex function, this will identify a potential countermeasure strategy to mitigate IR-induced cardiopulmonary toxicities.