Superoxide Mediates Acute Liver Injury in Irradiated Mice Lacking Sirtuin 3

作者：Coleman Mitchell C; Olivier Alicia K; Jacobus James A; Mapuskar Kranti A; Mao Gaowei; Martin Sean M; Riley Dennis P; Gius David; Spitz Douglas R^*

来源：Antioxidants and Redox Signaling, 2014, 20(9): 1423-1435.

DOI：10.1089/ars.2012.5091

Aims: This study determined whether acute radiation-induced liver injury seen in Sirtuin3(-/-) mice after exposure to Cs-137 -rays was mediated by superoxide anion (O-2(center dot-)). Results: Male wild-type (WT) and SIRT3(-/-) mice were given 2x2Gy whole-body radiation doses separated by 24h and livers were harvested 20h after the second dose. Ex vivo measurements in fresh frozen liver sections demonstrated 50% increases in dihydroethidium oxidation from SIRT3(-/-) animals, relative to WT animals, before irradiation, but this increase was not detected 20h after radiation exposure. In addition, irradiated livers from SIRT3(-/-) animals showed significant hydropic degeneration, loss of MitoTracker Green FM staining, increased immunohistochemical staining for 3-nitrotyrosine, loss of Ki67 staining, and increased mitochondrial localization of p53. These parameters of radiation-induced injury were significantly attenuated by an intraperitoneal injection of 2mg/kg of the highly specific superoxide dismutase mimic, GC4401, 30min before each fraction. Innovation: Sirtuin 3 (SIRT3) is believed to regulate mitochondrial oxidative metabolism and antioxidant defenses in response to acute radiation-induced liver injury. This work provides strong evidence for the causal role of O-2(center dot-) in the liver injury process initiated by whole-body irradiation in SIRT3(-/-) mice. Conclusion: These results support the hypothesis that O-2(center dot-) mediates acute liver injury in SIRT3(-/-) animals exposed to whole-body -radiation and suggest that GC4401 could be used as a radio-protective compound in vivo. Antioxid. Redox Signal. 20, 1423-1435.

• 出版日期2014-3-20
• 单位西北大学