Sirt3-dependent regulation of mitochondrial oxidative stress and apoptosis contributes to the dysfunction of pancreatic islets after severe burns

Background: Severe burns are often complicated with hyperglycemia caused by mitochondrial oxidative stress-related pancreatic islet dysfunction. Silent information regulator of transcription 3 (SIRT3) can regulate mitochondrial oxidative stress. However, the role and mechanism of SIRT3 on islet function after severe burns remain unclear. Therefore, this study aimed to investigate whether SIRT3 played a role in both mitochondrial oxidative stress in islets and mediating islet function post severe burns.

Methods: A mouse model of 30% total body surface area full-thickness burn and an in vitro MIN6 cell hypoxia model were established. SIRT3 KO mice were used to demonstrate further the role of SIRT3 in maintaining redox homeostasis and regulating islet function. Fasting blood glucose and glucose-stimulated Insulin secretion (GSIS) were detected to assess the islet function. The levels of mitochondrial ROS and deacetylation, and the activities of Mn-SOD and IDH2 were measured to evaluate oxidative stress. The mitochondrial membrane potential (MMP)was detected and the Apoptosis rate measured.

Results: In vitro MIN6 cells, the hypoxia treatment significantly reduced SIRT3 expression, resulting in increased deacetylation of Mn-SOD and IDH2, which further led to a higher level of mitochondrial ROS. In addition, hypoxia reduced MMP and increased Apoptosis rate, which impaired GSIS eventually. Knockdown of SIRT3 caused similar alterations. The hypoxia-induced high level of mitochondrial ROS and Apoptosis and impaired GSIS could be reversed by overexpression of SIRT3. Similarly, after severe burns, the expression of SIRT3 in islets decreased significantly with a high level of deacetylation of Mn-SOD, IDH2, mitochondrial ROS and Apoptosis, and islet dysfunction. Oxidative stress and Apoptosis also occurred in islets of SIRT3 KO mice, accompanied by islet dysfunction.

Conclusions: SIRT3 and downstream signalling are critical in modulating the islet function post severe burns by regulating mitochondrial oxidative stress and Apoptosis.

Apoptosis; Burns; Mitochondrial oxidative stress; Pancreatic islet; Sirt3.