Please wait a minute...
Journal of ZheJiang University(Medical Science)  2016, Vol. 45 Issue (3): 308-314    DOI: 10.3785/j.issn.1008-9292.2019.05.15
Zinc and autophagy
LIU Qiaoyun1, SHEN Hanming2, XIA Dajing1
1. Department of Toxicology, School of Public Health, Zhejiang University, Hangzhou 310058, China;
2. Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, 117597, Singapore
Download:   PDF(979KB)
Export: BibTeX | EndNote (RIS)      


Autophagy refers to a catabolic process,in which the damaged organelles or biological macromolecules, such as protein aggregates, are degraded via lysosome. The completion of autophagy depends on a series of autophagy-related genes (Atgs) and many upstream regulatory molecules. Zinc is an essential trace element, and plays an important role in the process of autophagy as a component of enzymes and structural proteins like zinc transporters or zinc finger protein. The regulation of autophagy is closely associated with the zinc ion homeostasis. In addition, many studies suggest that the protective effects of zinc on cells are likely to be done by autophagy. This review aims to summarize the current research progress and discuss the reciprocal regulation mechanism between zinc and autophagy, which may provide insights into the intricate roles of autophagy in diseases and find novel strategies for treatment and prevention of human diseases.

Key wordsZinc      Autophagy      Neoplasms      Review     
Received: 19 October 2015     
CLC:  R225  
Cite this article:

LIU Qiaoyun, SHEN Hanming, XIA Dajing. Zinc and autophagy. Journal of ZheJiang University(Medical Science), 2016, 45(3): 308-314.

URL:     OR



关键词: 锌,  自噬,  肿瘤,  综述 
[[1]]   MIZUSHIMA N, LEVINE B, CUERVO A M, et al. Autophagy fights disease through cellular self-digestion[J]. Nature, 2008, 451(7182):1069-1075.
[[2]]   MIZUSHIMA N, LEVINE B. Autophagy in mammalian development and differentiation[J]. Nat Cell Biol, 2010, 12(9): 823-830.
[[3]]   HIRANO T, MURAKAMI M, FUKADA T, et al. Roles of zinc and zinc signaling in immunity: zinc as an intracellular signaling molecule[J]. Adv Immunol, 2008, 97: 149-176.
[[4]]   LIUZZI J P, GUO L, YOO C, et al. Zinc and autophagy[J]. Biometals, 2014, 27(6): 1087-1096.
[[5]]   ZHAO Z, FUX B, GOODWIN M, et al. Autophagosome-independent essential function for the autophagy protein Atg5 in cellular immunity to intracellular pathogens[J]. Cell Host Microbe, 2008, 4(5): 458-469.
[[6]]   YANG Z, KLIONSKY D J. Eaten alive: a history of macroautophagy[J]. Nat Cell Biol, 2010, 12(9): 814-822.
[[7]]   JUNG C H, RO S H, CAO J, et al. mTOR regulation of autophagy[J]. FEBS Lett, 2010, 584(7):1287-1295.
[[8]]   REGGIORI F,SHINTANI T,NAIR U, et al. Atg9 cycles between mitochondria and the pre-autophagosomal structure in yeasts[J]. Autophagy, 2005, 1(2):101-109.
[[9]]   ITAKURA E, MIZUSHIMA N. Characterization of autophagosome formation site by a hierarchical analysis of mammalian Atg proteins[J]. Autophagy, 2010, 6(6): 764-776.
[[10]]   JUNG C H, JUN C B, RO S H, et al. ULK-Atg13-FIP200 complexes mediate mTOR signaling to the autophagy machinery[J]. Mol Biol Cell, 2009, 20(7): 1992-2003.
[[11]]   MIZUSHIMA N, KUMA A, KOBAYASHI Y, et al. Mouse Apg16L, a novel WD-repeat protein, targets to the autophagic isolation membrane with the Apg12-Apg5 conjugate[J]. J Cell Sci, 2003, 116(Pt 9): 1679-1688.
[[12]]   YU X, LONG Y C, SHEN H M. Differential regulatory functions of three classes of phosphatidylinositol and phosphoinositide 3-kinases in autophagy[J]. Autophagy, 2015, 11(10):1711-1728.
[[13]]   HE R, PENG J, YUAN P, et al. Divergent roles of BECN1 in LC3 lipidation and autophagosomal function[J]. Autophagy, 2015, 11(5): 740-747.
[[14]]   IN S, HONG C W, CHOI B, et al. Inhibition of mitochondrial clearance and Cu/Zn-SOD activity enhance 6-hydroxydopamine-induced neuronal apoptosis[J]. Mol Neurobiol, 2016, 53(1):777-791.
[[15]]   PAN R, TIMMINS G S, LIU W, et al. Autophagy mediates astrocyte death during zinc-potentiated ischimia-reperfusion injury[J]. Biol Trace Elem Res, 2015, 166(1): 89-95.
[[16]]   LIUZZI J P, YOO C. Role of zinc in the regulation of autophagy during ethanol exposure in human hepatoma cells[J]. Biol Trace Elem Res, 2013, 156(1-3): 350-356.
[[17]]   HWANG J J, KIM H N, KIM J, et al. Zinc(Ⅱ) ion mediates tamoxifen-induced autophagy and cell death in MCF-7 breast cancer cell line[J]. Biometals, 2010, 23(6): 997-1013.
[[18]]   ALAM S, KELLEHER S L. Cellular mechanisms of zinc dysregulation: a perspective on zinc homeostasis as an etiological factor in the development and progression of breast cancer[J]. Nutrients, 2012, 4(8): 875-903.
[[19]]   LI Y, ZHANG L, LI K, et al. ZNF32 inhibits autophagy through the mTOR pathway and protects MCF-7 cells from stimulus-induced cell death[J]. Sci Rep, 2015, 5: 9288.
[[20]]   HUNG H H, HUANG W P, PAN C Y. Dopamine-and zinc-induced autophagosome formation facilitates PC12 cell survival[J]. Cell Biol Toxicol, 2013, 29(6): 415-429.
[[21]]   SEO B R, LEE S J, CHO K S, et al. The zinc ionophore clioquinol reverses autophagy arrest in chloroquine-treated ARPE-19 cells and in APP/mutant presenilin-1-transfected Chinese hamster ovary cells[J]. Neurobiol Aging, 2015, 36(12):3228-3238.
[[22]]   KIM J, KUNDU M, VIOLLET B, et al. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1[J]. Nat Cell Biol, 2011,13(2): 132-141.
[[23]]   LEE S J, KOH J Y. Roles of zinc and metallothionein-3 in oxidative stress-induced lysosomal dysfunction, cell death, and autophagy in neurons and astrocytes[J]. Mol Brain, 2010,3(1): 30.
[[24]]   LICHTLEN P, SCHAFFNER W. The "metal transcription factor" MTF-1: biological facts and medical implications[J]. Swiss Med Wkly, 2002, 131(45-46): 647-652.
[[25]]   CARTHARIUS K, FRECH K, GROTE K, et al. MatInspector and beyond: promoter analysis based on transcription factor binding sites[J]. Bioinformatics, 2005, 21(13): 2933-2942.
[[26]]   KIM J H, JEON J, SHIN M, et al. Regulation of the catabolic cascade in osteoarthritis by the zinc-ZIP8-MTF1 axis[J]. Cell, 2014, 156(4): 730-743.
[[27]]   RYU M S, LANGKAMP-HENKEN B, CHANG S M, et al. Genomic analysis, cytokine expression, and microRNA profiling reveal biomarkers of human dietary zinc depletion and homeostasis[J]. Proc Natl Acad Sci U S A, 2011, 108(52): 20970-20975.
[[28]]   ENG B H, GUERIONT M L, EIDE D, et al. Sequence analyses and phylogenetic characterization of the ZIP family of metal ion transport proteins[J]. J Membr Biol, 1998, 166(1): 1-7.
[[29]]   PATRUSHEV N, SEIDEL-ROGOL B, SALAZAR G. Angiotensin Ⅱ requires zinc and downregulation of the zinc transporters ZnT3 and ZnT10 to induce senescence of vascular smooth muscle cells[J/OL]. PLoS One, 2012, 7(3):e33211.
[[30]]   BOSOMWORTH H J, ADLARD P A, FORD D, et al. Altered expression of ZnT10 in Alzheimer's disease brain[J/OL]. PLoS One, 2013, 8(5):e65475.
[[31]]   KAMBE T. An overview of a wide range of functions of ZnT and Zip zinc transporters in the secretory pathway[J]. Biosci Biotechnol Biochem, 2011, 75(6): 1036-1043.
[[32]]   KUMA A, MIZUSHIMA N, ISHIHARA N, et al. Formation of the approximately 350-kDa Apg12-Apg5.Apg16 multimeric complex, mediated by Apg16 oligomerization, is essential for autophagy in yeast[J]. J Biol Chem, 2002, 277(21): 18619-18625.
[[33]]   DING W X, LI M, CHEN X, et al. Autophagy reduces acute ethanol-induced hepatotoxicity and steatosis in mice[J]. Gastroenterology, 2010, 139(5): 1740-1752.
[[34]]   DERETIC V, SAITOH T, AKIRA S. Autophagy in infection, inflammation and immunity[J]. Nat Rev Immunol, 2013, 13(10): 722-737.
[[35]]   MANLEY S, WILLIAMS J A, DING W X. Role of p62/SQSTM1 in liver physiology and pathogenesis[J]. Exp Biol Med (Maywood), 2013, 238(5): 525-538.
[[36]]   Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls[J]. Nature, 2007, 447(7145): 661-678.
[[37]]   TAYLOR K M, VICHOVA P, JORDAN N, et al. ZIP7-mediated intracellular zinc transport contributes to aberrant growth factor signaling in antihormone-resistant breast cancer cells[J]. Endocrinology, 2008, 149(10): 4912-4920.
[[38]]   SUMMERSGILL H, ENGLAND H, LOPEZ-CASTEJON G, et al. Zinc depletion regulates the processing and secretion of IL-1β[J/OL]. Cell Death Dis, 2014, 5(1):e1040.
[1] CAI Cheng,WANG Jianping,ZHONG Zhifeng,DAI Zhihui,WANG Qinghua,DONG Wuzhen,SHI Hongqi,LIU Qingwei,DU Jinlin. Hypoxia-inducible factor-1α and CD133 predicts pathological complete response and survival for locally advanced rectal cancer patients after neoadjuvant chemoradiotherapy[J]. Journal of ZheJiang University(Medical Science), 2017, 46(1): 36-43.
[2] CHEN Gang,ZHANG Ding,YING Yacao,WANG Zhifeng,TAO Wei,ZHU Hao,ZHANG Jingfeng,PENG Zhiyi. Clinical investigation on transarterial chemoembolization with indigenous drug-eluting beads in treatment of unresectable hepatocellular carcinoma[J]. Journal of ZheJiang University(Medical Science), 2017, 46(1): 44-51.
[3] ZHENG Yanrong,ZHANG Xiangnan,CHEN Zhong. Research progress on mechanism of Nix-mediated mitophagy[J]. Journal of ZheJiang University(Medical Science), 2017, 46(1): 92-96.
[4] LI Wenlong,QU Haibin. Application progress on near infrared spectroscopy in quality control and process monitoring of traditional Chinese medicine[J]. Journal of ZheJiang University(Medical Science), 2017, 46(1): 80-88.
[5] GAO Siqian,SHEN Yongmei,GENG Funeng,LI Yanhua,GAO Jianqing. Research progress on the animal models and treatment strategies of diabetic foot ulcer[J]. Journal of ZheJiang University(Medical Science), 2017, 46(1): 97-105.
[6] WANG Ying,WANG Yi,CHEN Zhong. The role of central cholinergic system in epilepsy[J]. Journal of ZheJiang University(Medical Science), 2017, 46(1): 15-21.
[7] GAO Siqian,SHEN Yongmei,GENG Funeng,Yanhua LI,Jianqing GAO. Temporal lobe epilepsy and adult hippocampal neurogenesis[J]. Journal of ZheJiang University(Medical Science), 2017, 46(1): 97-105.
[8] FENG Sheng, CHEN Jijun, ZHENG Yichun. Research progress on the effect of glucocorticoid receptor signaling pathways in bladder cancer[J]. Journal of ZheJiang University(Medical Science), 2016, 45(6): 655-660.
[9] LI Tongyu, LIANG Ping. Research progress on disease models and gene therapy of Duchenne muscular dystrophy[J]. Journal of ZheJiang University(Medical Science), 2016, 45(6): 648-654.
[10] XIA Guangfa, ZHU Juanying, YUAN Jun, CAO Bo, TANG Jie, CHEN Yiding. Efficacy of adjuvant endocrine therapy in breast cancer patients with a positive-to-negative switch of hormone receptor status after neoadjuvant chemotherapy[J]. Journal of ZheJiang University(Medical Science), 2016, 45(6): 614-619.
[11] CAO Peng, LENG Dongjin, LI Ying, ZHANG Ziwei, LIU Lei, LI Xiaoyan. Progress on anti-tumor molecular mechanisms of dihydroartemisinin[J]. Journal of ZheJiang University(Medical Science), 2016, 45(5): 501-507.
[12] LI Tingting, KE Yuehai, CHENG Hongqiang. Reasearch progress on the role of neutrophils in asthma[J]. Journal of ZheJiang University(Medical Science), 2016, 45(5): 544-549.
[13] WANG Xue, ZHANG Yuchuan, CHEN Wei. Research progress on the role of TANK-binding kinase 1 in anti-virus innate immune response[J]. Journal of ZheJiang University(Medical Science), 2016, 45(5): 550-557.
[14] DU Miaomiao, MA Gaigai, SHI Yuping. Research progress on pharmacotherapy of calcific aortic valve disease[J]. Journal of ZheJiang University(Medical Science), 2016, 45(4): 432-438.
[15] ZHENG Jiangjiang, ZHU Yin, LI Changshui, LI Yinya, NIE Qianqian, ZHU Ziling, DENG Hong. Expression of CD10 in tumor-associated fibroblast of cancerized or recurrent colorectal adenomas[J]. Journal of ZheJiang University(Medical Science), 2016, 45(4): 335-341.