The role of MnSOD and sirtuin 3 in thymocyte responses to radiation and lymphomagenesis

Abstract

Manganese superoxide dismutase (MnSOD), is a mitochondria-localized antioxidant enzyme that scavenges superoxide anions generated in the respiratory chains, has been known to play an important role in the radioprotection, and function as a tumor suppressor gene in many types of cancer. Sirtuin 3 (Sirt3) is a mitochondrial NADdependent deacetylase that regulates mitochondrial oxidative metabolism, MnSOD activity, and tumorigenesis. The current study was designed to examine the role of MnSOD and Sirt3 in regulating mitochondrial metabolism and steady-state levels of O2 •in thymocyte responses to ionizing radiation (IR) and lymphomagenesis. Loss of MnSOD in thymocytes resulted in the decreased levels of viability when mice were exposed to 0.1 or 1 Gy Cs radiation. In contrast, loss of Sirt3 did not affect thymocyte radiosensitivity or radiation-induced superoxide levels when mice were exposed to a single dose of Cs radiation (0.1 or 1 Gy). Interestingly, the Sirt3 thymocytes demonstrated a compromised ability to induce an adaptive response following whole body exposure to a 0.1 Gy dose of Cs radiation when challenged 4 h later with a 1.5 Gy dose of Cs radiation. Of note, both Sirt3 and MnSOD thymocytes did not demonstrate increased T cell lymphoma in C57BL/6 mice at 15-18 months following low dose (0.1 Gy or 1 Gy) radiation exposure to low linear energy transfer (LET) Cs or high LET 300 MeV/n Silicon (67 kev/μM) irradiation. Interestingly, the loss of Sirt3 in Bax overexpressing transgenic thymocytes did cause significant alterations in mitochondrial oxidative metabolism including increased levels of superoxide, increased mitochondrial membrane potential, and increased oxygen consumption, as well as decreased levels of MnSOD activity and decreased steady-state levels of ATP. Sirt3 was also found to be upregulated in Lck-Bax transgenic pre-malignant thymocytes, and downregulation of Sirt3 was noted in lymphomas from Lck-Bax mice. Furthermore, a significant acceleration of thymic lymphoma development was observed in Lck-Bax transgenic animals lacking Sirt3. In