PMID- 35357035 OWN - NLM STAT- MEDLINE DCOM- 20220401 LR - 20220508 IS - 1530-6860 (Electronic) IS - 0892-6638 (Linking) VI - 36 IP - 5 DP - 2022 May TI - cGAS-STING mediates cytoplasmic mitochondrial-DNA-induced inflammatory signal transduction during accelerated senescence of pancreatic beta-cells induced by metabolic stress. PG - e22266 LID - 10.1096/fj.202101988R [doi] AB - Type 2 diabetes mellitus (T2DM) is an age-related disease characterized by impaired pancreatic beta cell function and insulin resistance. Recent studies have shown that the accumulation of senescent beta cells under metabolic stress conditions leads to the progression of T2DM, while senolysis can improve the prognosis. However, the specific mechanism of beta cell senescence is still unclear. In this study, we found that the increased load of senescence pancreatic beta cells in both older mice and obese mice induced by high-fat diet (HFD) (DIO mice) was accompanied by activation of the Cyclic GMP-AMP synthase (cGAS) - stimulator of interferon genes (STING) pathway and using cGAS or STING small interfering RNA or STING inhibitor C176 to downregulate this pathway reduced the senescence-associated secretion profile (SASP) and senescence of Min6 cells treated with palmitic acid or hydrogen peroxide. C176 intervention in DIO mice also significantly reduced the inflammation and senescence of the islets, thereby protecting the function of pancreatic beta cell and glucose metabolism. Our study further revealed that mitochondrial DNA (mtDNA) leakage under metabolic stress conditions was critical for the activation of the cGAS-STING pathway, which can be reversed by the mtDNA depleting agent ethidium bromide. Consistently, mtDNA leakage was more severe in older mice and was accelerated by a chronic HFD. In conclusion, we demonstrate that cytoplasmic mtDNA activates the cGAS-STING pathway to mediate SASP during the accelerated senescence of pancreatic beta-cells induced by metabolic stress, and this process can be downregulated by the STING inhibitor C176. CI - (c) 2022 Federation of American Societies for Experimental Biology. FAU - Hu, Huiqing AU - Hu H AD - Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China. FAU - Zhao, Ruxing AU - Zhao R AD - Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China. AD - Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan, China. AD - Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine & Health, Jinan, China. AD - Jinan Clinical Research Center for Endocrine and Metabolic Diseases, Jinan, China. FAU - He, Qin AU - He Q AD - Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China. FAU - Cui, Chen AU - Cui C AD - Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China. FAU - Song, Jia AU - Song J AD - Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China. FAU - Guo, Xinghong AU - Guo X AD - Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China. FAU - Zang, Nan AU - Zang N AD - Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China. FAU - Yang, Mengmeng AU - Yang M AD - Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China. FAU - Zou, Ying AU - Zou Y AD - Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China. FAU - Yang, Jingwen AU - Yang J AD - Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China. FAU - Li, Jinquan AU - Li J AD - Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China. FAU - Wang, Liming AU - Wang L AD - Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China. FAU - Xia, Longqing AU - Xia L AD - Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China. FAU - Wang, Lingshu AU - Wang L AD - Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China. AD - Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan, China. AD - Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine & Health, Jinan, China. AD - Jinan Clinical Research Center for Endocrine and Metabolic Diseases, Jinan, China. FAU - He, Falian AU - He F AD - Nuolai Biomedical Technology Co., Ltd., Taian, China. FAU - Hou, Xinguo AU - Hou X AD - Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China. AD - Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan, China. AD - Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine & Health, Jinan, China. AD - Jinan Clinical Research Center for Endocrine and Metabolic Diseases, Jinan, China. FAU - Yan, Fei AU - Yan F AD - Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China. AD - Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan, China. AD - Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine & Health, Jinan, China. AD - Jinan Clinical Research Center for Endocrine and Metabolic Diseases, Jinan, China. FAU - Chen, Li AU - Chen L AUID- ORCID: 0000-0001-7795-6498 AD - Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China. AD - Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan, China. AD - Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine & Health, Jinan, China. AD - Jinan Clinical Research Center for Endocrine and Metabolic Diseases, Jinan, China. AD - Nuolai Biomedical Technology Co., Ltd., Taian, China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - United States TA - FASEB J JT - FASEB journal : official publication of the Federation of American Societies for Experimental Biology JID - 8804484 RN - 0 (DNA, Mitochondrial) RN - 0 (Membrane Proteins) RN - EC 2.7.7.- (Nucleotidyltransferases) SB - IM MH - Animals MH - DNA, Mitochondrial/genetics/metabolism MH - *Diabetes Mellitus, Type 2 MH - *Insulin-Secreting Cells/metabolism MH - Membrane Proteins/genetics/metabolism MH - Mice MH - Nucleotidyltransferases/genetics/metabolism MH - Signal Transduction MH - Stress, Physiological OTO - NOTNLM OT - SASP OT - cGAS-STING pathway OT - pancreatic beta cell function OT - senescence OT - type 2 diabetes mellitus EDAT- 2022/04/01 06:00 MHDA- 2022/04/02 06:00 CRDT- 2022/03/31 08:38 PHST- 2022/02/21 00:00 [revised] PHST- 2021/12/28 00:00 [received] PHST- 2022/03/08 00:00 [accepted] PHST- 2022/03/31 08:38 [entrez] PHST- 2022/04/01 06:00 [pubmed] PHST- 2022/04/02 06:00 [medline] AID - 10.1096/fj.202101988R [doi] PST - ppublish SO - FASEB J. 2022 May;36(5):e22266. doi: 10.1096/fj.202101988R.