Abstract IA-023: The role of sirtuins in radiation-induced cardiac dysfunction

Currently there is no way to reliably predict who is at higher or lower risk of cardiac toxicity from radiation, and the critical factors that alter radiation-induced heart disease are not completely clear. The heart produces and uses the most energy of all organs, with >90% of its energy produced via mitochondrial respiration. To maintain this energy output, ~30% of the heart volume is made up of mitochondria in cardiomyocytes. Such a high metabolic rate produces increased levels of reactive oxygen species (ROS), which have the potential to cause serious oxidative damage to the heart. Antioxidant enzymes such as superoxide dysmutases (SODs), catalase, and glutathione peroxidase can help to protect against ROS-mediated damage by converting superoxide to hydrogen peroxidase, and then hydrogen peroxide to water. Oxidative stressors, including therapeutic radiation therapy, have been shown to lead to long-term effects on mitochondrial function, as measured by excess formation of ROS including superoxide, mitochondrial-related gene expression, and altered mitochondrial morphology and functions such as mitochondrial respiration, pyruvate metabolism, and ion and lipid transport. While a potential link between aging-related signaling pathways, metabolic homeostasis, and radiation-induced normal tissue damage has recently been suggested, rigorous mechanistic data to support this intriguing idea has been limited. Mitochondrial detoxification pathways, which are dysregulated in normal tissues by radiation, lead to increased ROS levels and the disruption of mitochondrial reparative pathways. SIRT3 is one of three mitochondrial-located sirtuin proteins. SIRT3 is the primary deacetylase of mitochondrial proteins, and its deacetylase activity plays a key role in maintaining mitochondrial energy metabolism equilibrium and defending against cellular damage that occurs with aging. Lysine acetylation is an important post-translational modification that can regulate the function of mitochondrial proteins. The acetylation status of key mitochondrial detoxification proteins, which are Sirt3 deacetylation targets, may be dysregulated in normal tissue following radiation exposure. Loss of SIRT3 can dysregulate mitochondrial detoxification and metabolism, leading to the accumulation of cellular damage. Sirt3 KO mice demonstrate enhanced mitochondrial dysfunction, and Sirt3 KO mice exhibit enhanced doxorubicin- and aortic constriction-induced cardiac hypertrophy. In addition, Sirt3 KO MEFs and livers are more sensitive to radiation and exhibit increased mitochondrial superoxide levels. However, the role of sirtuins in radiation-induced cardiac injury has not been examined. Here we review data on the potential role of sirtuins, and in particular Sirt3, on radiation-induced cardiac function. Citation Format: Carmen Bergom. The role of sirtuins in radiation-induced cardiac dysfunction [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr IA-023.