SENP2 regulates mitochondrial function and insulin secretion in pancreatic β cells

• Published in: Experimental & molecular medicine Vol. 54; no. 1; pp. 72 - 80
• Main Authors: Nan, Jinyan, Lee, Ji Seon, Moon, Joon Ho, Lee, Seung-Ah, Park, Young Joo, Lee, Dong-Sup, Chung, Sung Soo, Park, Kyong Soo
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.01.2022; Springer Nature B.V; 생화학분자생물학회
• Subjects: 14/28; 42/109; 42/70; 631/337/458/1733; 631/80/304; 631/80/458/538; 64/110; 64/60; 692/163/2743/137; 82/29; 82/51; 82/80; Adipogenesis; Animals; Beta cells; Biomedical and Life Sciences; Biomedicine; Cell culture; Cysteine Endopeptidases - genetics; Cysteine Endopeptidases - metabolism; Diabetes; Diabetes mellitus (non-insulin dependent); Glucose; Glucose - metabolism; Glucose tolerance; Insulin; Insulin - metabolism; Insulin Secretion; Insulin-Secreting Cells - metabolism; Investigations; Lipid metabolism; Medical Biochemistry; Metabolism; Mice; Mitochondria; Mitochondria - metabolism; Mitochondrial Proteins - metabolism; Molecular Medicine; Oxygen consumption; Palmitic acid; Pancreas; Peptide Hydrolases - metabolism; Phosphorylation; Protein turnover; Proteins; Secretion; Skeletal muscle; Stem Cells; Ubiquitin; 생화학
• ISSN: 1226-3613; 2092-6413
• DOI: 10.1038/s12276-021-00723-7

Increasing evidence has shown that small ubiquitin-like modifier (SUMO) modification plays an important role in metabolic regulation. We previously demonstrated that SUMO-specific protease 2 (SENP2) is involved in lipid metabolism in skeletal muscle and adipogenesis. In this study, we investigated the function of SENP2 in pancreatic β cells by generating a β cell-specific knockout ( Senp2 -βKO) mouse model. Glucose tolerance and insulin secretion were significantly impaired in the Senp2 -βKO mice. In addition, glucose-stimulated insulin secretion (GSIS) was decreased in the islets of the Senp2 -βKO mice without a significant change in insulin synthesis. Furthermore, islets of the Senp2 -βKO mice exhibited enlarged mitochondria and lower oxygen consumption rates, accompanied by lower levels of S616 phosphorylated DRP1 (an active form of DRP1), a mitochondrial fission protein. Using a cell culture system of NIT-1, an islet β cell line, we found that increased SUMO2/3 conjugation to DRP1 due to SENP2 deficiency suppresses the phosphorylation of DRP1, which possibly induces mitochondrial dysfunction. In addition, SENP2 overexpression restored GSIS impairment induced by DRP1 knockdown and increased DRP1 phosphorylation. Furthermore, palmitate treatment decreased phosphorylated DRP1 and GSIS in β cells, which was rescued by SENP2 overexpression. These results suggest that SENP2 regulates mitochondrial function and insulin secretion at least in part by modulating the phosphorylation of DRP1 in pancreatic β cells. Glucose metabolism: regulation of insulin secretion A protein called SENP2 plays a critical role in regulating secretion of insulin, the hormone that regulates blood sugar. Although SENP2 had been associated with type 2 diabetes, its role in regulating insulin secretion remained unclear. Kyong Soo Park and Sung Soo Chung at Seoul National University, South Korea, investigated how SENP2 regulates glucose metabolism using a mouse model that has SENP2-deficient pancreatic β cells. In the SENP2-deficient mice pancreatic β cells produced sufficient insulin but did not properly secrete it, and the cellular powerhouses, the mitochondria, were enlarged. Further investigation showed that SENP2 regulates a protein called DRP1 that triggers mitochondria to divide when they get too large. Boosting levels of SENP2 restored levels of functional DRP1 and boosted insulin secretion. These results improve our understanding of glucose metabolism, insulin-secreting cells, and diabetes.