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Mitochondrial superoxide production during the early and late radiation response is increasingly recognized as a critical driver of oxidative damage and injury processes in mammalian cells. The role of Sirtuin 3, a key mitochondrial regulatory deacetylase, in preventing mitochondrial superoxide generation in conditions of nutrient and oxidative stress may be critical during the radiation response in mammalian liver. Because several tumor types express lower than normal levels of Sirtuin 3, the involvement of Sirtuin 3 in the radiation response may also provide clues to improving cancer radiation therapy and understanding the process of carcinogenesis. Studies of how the SIRT3 loss impacts the hepatic radiation response may also provide insight into the role of superoxide in normal liver physiology as well as in conditions of pathology. Increased superoxide production has largely been associated with disease, but oftentimes without clear demonstration of mechanism or even clear descriptions of pathogenesis. Here we identify a target of Sirtuin 3, the mitochondrial antioxidant enzyme manganese superoxide dismutase, and delineate the role that Sirtuin 3-mediated increases in manganese superoxide dismutase may be playing in the prevention of injury following biologically relevant doses of low linear energy transfer and high linear energy transfer radiation types including Cs-137 and Fe and Si particle radiation. Loss of Sirtuin 3 appears to correlate with decreases in hepatocellular carcinoma 16 months after 0.1 and 1 Gy doses of particle radiation known to increase hepatocellular carcinoma rates. These results indicate that Sirtuin 3 is a critical regulator of superoxide metabolism in the liver following whole body irradiation.