药学学报, 2017, 52(5): 667-672
王悦, 刘率男, 申竹芳. 线粒体-内质网动态关联与胰岛β细胞功能稳态[J]. 药学学报, 2017, 52(5): 667-672.
WANG Yue, LIU Shuai-nan, SHEN Zhu-fang. Dynamic associations of mitochondria-endoplasmic reticulum in maintenance of pancreatic beta cell homeostasis[J]. Acta Pharmaceutica Sinica, 2017, 52(5): 667-672.

王悦, 刘率男, 申竹芳
中国医学科学院、北京协和医学院药物研究所, 天然药物活性物质与功能国家重点实验室, 北京 100050
关键词:    线粒体      内质网      胰岛β细胞      物质代谢      2型糖尿病     
Dynamic associations of mitochondria-endoplasmic reticulum in maintenance of pancreatic beta cell homeostasis
WANG Yue, LIU Shuai-nan, SHEN Zhu-fang
State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
The appropriate regulation of intracellular bioenergy and nutrient metabolism is a basic requirement for proper function and survival of pancreatic beta cells, where mitochondria-endoplasmic reticulum (ER)-associations play crucial roles. Mitochondria are changed dynamically according to intracellular energy and nutrients, which provides material foundation for energy homeostasis; while ER regulates metabolic enzymes and protein synthesis in different pathways. This review sheds light upon the development of mitochondria-ER associations and its role in the regulation of insulin secretion in pancreatic beta cell. The impact on beta cell viability is discussed. Interruption of calcium and redox oxidative species results in reduction of glucose-stimulated insulin secretion, while intracellular calcium levels could be partial altered by depleting calcium from the ER. Given the tight link between ER and mitochondria, the association are crucial to the homeostasis and are an indicator of overall beta cell status, with a potential as a novel drug target for treatment of type 2 diabetes mellitus.
Key words:    mitochondria    endoplasmic reticulum    pancreatic beta cell    nutrient metabolism    type 2 diabetes mellitus   
收稿日期: 2016-11-24
DOI: 10.16438/j.0513-4870.2016-1132
基金项目: 国家自然科学基金资助项目(81202574);北京市自然科学基金资助项目(7132162);重大新药创制国家科技重大专项资助项目(2012ZX09301002-004).
通讯作者: 申竹芳,Tel:86-10-83172669,E-mail:shenzhf@imm.ac.cn
Email: shenzhf@imm.ac.cn
PDF(297KB) Free
王悦  在本刊中的所有文章
刘率男  在本刊中的所有文章
申竹芳  在本刊中的所有文章

[1] Rutter GA, Pinton P. Mitochondria-associated endoplasmic reticulum membranes in insulin signaling [J]. Diabetes, 2014, 63: 3163-3165.
[2] Liu X, Hajnóczky G. Altered fusion dynamics underlie unique morphological changes in mitochondria during hypoxia-reoxygenation stress [J]. Cell Death Differ, 2011, 18: 1561-1572.
[3] Liesa M, Palacín M, Zorzano A. Mitochondrial dynamics in mammalian health and disease [J]. Physiol Rev, 2009, 89: 799-845.
[4] Yin F, Cadenas E. Mitochondria: the cellular hub of the dynamic coordinated network [J]. Antioxid Redox Signal, 2015, 22: 961-964.
[5] Wang C, Du W, Su QP, et al. Dynamic tubulation of mitochondria drives mitochondrial network formation [J]. Cell Res, 2015, 25: 1108-1120.
[6] Corkey BE, Deeney JT, Yaney GC, et al. The role of long-chain fatty acyl-CoA esters in β-cell signal transduction [J]. J Nutr, 2000, 130: 299S-304S.
[7] Rutter GA. Nutrient-secretion coupling in the pancreatic islet β-cell: recent advances [J]. Mol Aspects Med, 2001, 22: 247-284.
[8] Pi J, Zhang Q, Fu J, et al. ROS signaling, oxidative stress and Nrf2 in pancreatic β-cell function [J]. Toxicol Appl Pharmacol, 2010, 244: 77-83.
[9] Buteau J, Roduit R, Susini S, et al. Glucagon-like peptide-1 promotes DNA synthesis, activates phosphatidylinositol 3-kinase and increases transcription factor pancreatic and duodenal homeobox gene 1 (PDX-1) DNA binding activity in β (INS-1)-cells [J]. Diabetologia, 1999, 42: 856-864.
[10] Kibbey RG, Pongratz RL, Romanelli AJ, et al. Mitochondrial GTP regulates glucose-stimulated insulin secretion [J]. Cell Metab, 2007, 5: 253-264.
[11] Floyd JC Jr, Fajans SS, Conn JW, et al. Stimulation of insulin secretion by amino acids [J]. J Clin Invest, 1966, 45: 1487-1502.
[12] Poitout V, Robertson RP. Glucolipotoxicity: fuel excess and β-cell dysfunction [J]. Endocr Rev, 2008, 29: 351-366.
[13] Chang-Chen KJ, Mullur R, Bernal-Mizrachi E. β-Cell failure as a complication of diabetes [J]. Rev Endocr Metab Disord, 2008, 9: 329-343.
[14] Prentki M, Nolan CJ. Islet β cell failure in type 2 diabetes [J]. J Clin Invest, 2006, 116: 1802-1812.
[15] Gilon P, Chae HY, Rutter GA, et al. Calcium signaling in pancreatic β-cells in health and in type 2 diabetes [J]. Cell Calcium, 2014, 56: 340-361.
[16] Pi J, Bai Y, Zhang Q, et al. Reactive oxygen species as a signal in glucose-stimulated insulin secretion [J]. Diabetes, 2007, 56: 1783-1791.
[17] Robertson RP. Chronic oxidative stress as a central mechanism for glucose toxicity in pancreatic islet beta cells in diabetes [J]. J Biol Chem, 2004, 279: 42351-42354.
[18] Supale S, Li N, Brun T, et al. Mitochondrial dysfunction in pancreatic β cells [J]. Trends Endocrinol Metab, 2012, 23: 477-487.
[19] Liu SN, Liu Q, Shen ZF. Metformin improves β-cell dysfunction by regulating inflammation production, ion and hormone homeostasis of pancreas in diabetic KKAy mice [J]. Acta Pharm Sin (药学学报), 2014, 49: 1554-1562.
[20] Affourtit C, Brand MD. Stronger control of ATP/ADP by proton leak in pancreatic β-cells than skeletal muscle mitochondria [J]. Biochem J, 2006, 393: 151-159.
[21] Irles E, Ñeco P, Lluesma M, et al. Enhanced glucose-induced intracellular signaling promotes insulin hypersecretion: pancreatic β-cell functional adaptations in a model of genetic obesity and prediabetes [J]. Mol Cell Endocrinol, 2015, 404: 46-55.
[22] Chan DC. Mitochondria: dynamic organelles in disease, aging, and development [J]. Cell, 2006, 125: 1241-1252.
[23] Ishihara H, Asano T, Tsukuda K, et al. Pancreatic β cell line MIN6 exhibits characteristics of glucose metabolism and glucose-stimulated insulin secretion similar to those of normal islets [J]. Diabetologia, 1993, 36: 1139-1145.
[24] Wang Y, Liu SN, Shen ZF. Up-regulation of Sirtuin 5 contributes to protection for mouse pancreatic beta cell against apoptosis induced by high fat and glucose [J]. Diabetes Metab Res Rev, 2014, 30: 50-51.
[25] Molina AJ, Wikstrom JD, Stiles L, et al. Mitochondrial networking protects β-cells from nutrient-induced apoptosis [J]. Diabetes, 2009, 58: 2303-2315.
[26] Seifert EL, Estey C, Xuan JY, et al. Electron transport chain-dependent and -independent mechanisms of mitochondrial H2O2 emission during long-chain fatty acid oxidation [J]. J Biol Chem, 2010, 285: 5748-5758.
[27] Echtay KS, Roussel D, St-Pierre J, et al. Superoxide activates mitochondrial uncoupling proteins [J]. Nature, 2002, 415: 96-99.
[28] Matthias A, Ohlson KBE, Fredriksson JM, et al. Thermogenic responses in brown fat cells are fully UCP1-dependent. UCP2 or UCP3 do not substitute for UCP1 in adrenergically or fatty acid-induced thermogenesis [J]. J Biol Chem, 2000, 275: 25073-25081.
[29] Shabalina IG, Backlund EC, Bar-Tana J, et al. Within brown-fat cells, UCP1-mediated fatty acid-induced uncoupling is independent of fatty acid metabolism [J]. Biochim Biophys Acta, 2008, 1777: 642-650.
[30] Choi SY, Huang P, Jenkins GM, et al. A common lipid links Mfn-mediated mitochondrial fusion and SNARE-regulated exocytosis [J]. Nat Cell Biol, 2006, 8: 1255-1262.
[31] Anello M, Lupi R, Spampinato D, et al. Functional and morphological alterations of mitochondria in pancreatic beta cells from type 2 diabetic patients [J]. Diabetologia, 2005, 48: 282-289.
[32] Laybutt DR, Preston AM, Åkerfeldt MC, et al. Endoplasmic reticulum stress contributes to beta cell apoptosis in type 2 diabetes [J]. Diabetologia, 2007, 50: 752-763.
[33] Lin N, Chen H, Zhang H, et al. Mitochondrial reactive oxygen species (ROS) inhibition ameliorates palmitate-induced INS-1 β cell death [J]. Endocrine, 2012, 42: 107-117.
[34] Lahiri S, Chao JT, Tavassoli S, et al. A conserved endoplasmic reticulum membrane protein complex (EMC) facilitates phos-pholipid transfer from the ER to mitochondria [J]. PLoS Biol, 2014, 12: e1001969.
[35] Rizzuto R, Pinton P, Carrington W, et al. Close contacts with the endoplasmic reticulum as determinants of mitochondrial Ca2+ responses [J]. Science, 1998, 280: 1763-1766.
[36] Achleitner G, Gaigg B, Krasser A, et al. Association between the endoplasmic reticulum and mitochondria of yeast facilitates interorganelle transport of phospholipids through membrane contact [J]. Eur J Biochem, 1999, 264: 545-553.
[37] de Brito OM, Scorrano L. Mitofusin 2 tethers endoplasmic reticulum to mitochondria [J]. Nature, 2008, 456: 605-610.
[38] Cerqua C, Anesti V, Pyakurel A, et al. Trichoplein/mitostatin regulates endoplasmic reticulum-mitochondria juxtaposition [J]. EMBO Rep, 2010, 11: 854-860.
[39] Stroud DA, Oeljeklaus S, Wiese S, et al. Composition and topology of the endoplasmic reticulum-mitochondria encounter structure [J]. J Mol Biol, 2011, 413: 743-750.
[40] Toulmay A, Prinz WA. Lipid transfer and signaling at organelle contact sites: the tip of the iceberg [J]. Curr Opin Cell Biol, 2011, 23: 458-463.
[41] Kopec KO, Alva V, Lupas AN. Homology of SMP domains to the TULIP superfamily of lipid-binding proteins provides a structural basis for lipid exchange between ER and mitochon-dria [J]. Bioinformatics, 2010, 26: 1927-1931.
[42] Leal NS, Schreiner B, Pinho CM, et al. Mitofusin-2 knock-down increases ER-mitochondria contact and decreases amyloid β-peptide production [J]. J Cell Mol Med, 2016, 20: 1686-1695.
[43] Lewis SC, Uchiyama LF, Nunnari J. ER-mitochondria contacts couple mtDNA synthesis with mitochondrial division in human cells [J]. Science, 2016, 353: aaf5549.
[44] Roy S, Trudeau K, Roy S, et al. Mitochondrial dysfunction and endoplasmic reticulum stress in diabetic retinopathy: mechanistic insights into high glucose-induced retinal cell death [J]. Curr Clin Pharmacol, 2013, 8: 278-284.
[45] Rocha M, Diaz-Morales N, Rovira-Llopis S, et al. Mito-chondrial dysfunction and endoplasmic reticulum stress in diabetes [J]. Curr Pharm Des, 2016, 22: 2640-2649.
[46] Li L, Pan ZF, Huang X, et al. Junctophilin 3 expresses in pancreatic beta cells and is required for glucose-stimulated insulin secretion [J]. Cell Death Dis, 2016, 7: e2275.
[47] Ozcan L, Tabas I. Calcium signalling and ER stress in insulin resistance and atherosclerosis [J]. J Intern Med, 2016, 280: 457-464.
[48] Wiederkehr A, Wollheim CB. Mitochondrial signals drive insulin secretion in the pancreatic β-cell [J]. Mol Cell Endocrinol, 2012, 353: 128-137.
[49] Sebastián D, Hernández-Alvarez MI, Segalés J, et al. Mitofusin 2 (Mfn2) links mitochondrial and endoplasmic reticulum function with insulin signaling and is essential for normal glucose homeostasis [J]. Proc Natl Acad Sci U S A, 2012, 109: 5523-5528.
[50] Tubbs E, Theurey P, Vial G, et al. Mitochondria-associated endoplasmic reticulum membrane (MAM) integrity is required for insulin signaling and is implicated in hepatic insulin resistance [J]. Diabetes, 2014, 63: 3279-3294.
[51] Kahn SE, Zraika S, Utzschneider KM, et al. The β cell lesion in type 2 diabetes: there has to be a primary functional abnormality [J]. Diabetologia, 2009, 52: 1003-1012.
[52] Kulkarni RN, Brüning JC, Winnay JN, et al. Tissue-specific knockout of the insulin receptor in pancreatic beta cells creates an insulin secretory defect similar to that in type 2 diabetes [J]. Cell, 1999, 96: 329-339.
1.陈致瑜, 刘率男, 罗振华, 孙素娟, 申竹芳, 聂瑛洁.二甲双胍对高脂饮食诱导的2型糖尿病小鼠胰岛β细胞功能的改善及机制探讨[J]. 药学学报, 2017,52(10): 1561-1567