SIRT3基因多态性与年龄相关性疾病的研究进展
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摘要
Sirtuins家族是一类高度保守的NAD+依赖性Ⅲ组蛋白去乙酰化酶,通过催化一系列脱乙酰和ADP核糖基化的非组蛋白而构成了正常与病理条件下代谢完整性、细胞存活和细胞同源性的表观遗传调控的一个重要方面。作为Sirtuins家族具有最强去乙酰化酶活性的一员,SIRT3 (Sirtuin 3)凭借其广泛的调控线粒体形态与功能的能力,成为近几年来的研究热点。最近的一些研究发现,SIRT3过表达可以在体内及体外模型中预防某些神经紊乱,如衰老、帕金森病、阿尔茨海默病、卒中等年龄相关性疾病。目前人们较少关注SIRT3基因多态性在年龄相关疾病中的作用。因此,本文将系统性地对SIRT3基因的结构定位、细胞代谢及其在年龄相关性疾病中的作用作一总结。
Sirtuins family is a highly conserved class of NAD+dependent histone deacetylase III. It is an important aspect of epigenetic regulation of metabolic integrity, cell survival and cell homology under normal and pathological conditions by catalyzing a series of deacetylated and ADP ribosylated non-histones. As a member of the Sirtuins family with the strongest deacetylase activity, SIRT3(Sirtuin 3) has become a research hotspot in recent years because of its extensive ability to regulate the morphology and function of mitochondria. Recent studies have found that SIRT3 overexpression can prevent some neurological disorders in vivo and in vitro models, such as aging, Parkinson's disease, Alzheimer's disease, stroke and other age-related diseases. At present, little attention has been paid to the role of SIRT3 gene polymorphism in age-related diseases. Therefore, this article will systematically summarize the structural localization, cell metabolism of SIRT3 gene and its role in age-related diseases.
Sirtuins family is a highly conserved class of NAD+dependent histone deacetylase III. It is an important aspect of epigenetic regulation of metabolic integrity, cell survival and cell homology under normal and pathological conditions by catalyzing a series of deacetylated and ADP ribosylated non-histones. As a member of the Sirtuins family with the strongest deacetylase activity, SIRT3(Sirtuin 3) has become a research hotspot in recent years because of its extensive ability to regulate the morphology and function of mitochondria. Recent studies have found that SIRT3 overexpression can prevent some neurological disorders in vivo and in vitro models, such as aging, Parkinson's disease, Alzheimer's disease, stroke and other age-related diseases. At present, little attention has been paid to the role of SIRT3 gene polymorphism in age-related diseases. Therefore, this article will systematically summarize the structural localization, cell metabolism of SIRT3 gene and its role in age-related diseases.
引文
[1]PARK S,MORI R,SHIMOKAWA I.Do sirtuins promote mammalian longevity?A critical review on its relevance to the longevity effect induced by calorie restriction[J].Mol Cells,2013,35(6):474-480.
[2]VERDIN E,HIRSCHEY MD,FINLEY LW,et al.Sirtuin regulation of mitochondria:energy production,apoptosis,and signaling[J].Trends Biochem Sci,2010,35(12):669-675.
[3]AVALOS JL,CELIC I,MUHAMMAD S,et al.Structure of a Sir2 enzyme bound to an acetylated p53 peptide[J].Mol Cell,2002,10(3):523-535.
[4]JIN L,WEI W,JIANG Y,et al.Crystal structures of human SIRT3displaying substrate-induced conformational changes[J].J Biol Chem,2009,284(36):24394-24405.
[5]LOMBARD DB,ALT FW,CHENG HL,et al.Mammalian Sir2 homolog SIRT3 regulates global mitochondrial lysine acetylation[J].Mol Cell Biol,2007,27(24):8807-8814.
[6]IWAHARA T,BONASIO R,NARENDRA V,et al.SIRT3 functions in the nucleus in the control of stress-related gene expression[J].Mol Cell Biol,2012,32(24):5022-5034.
[7]JIN L,GALONEK H,ISRAELIAN K,et al.Biochemical characterization,localization,and tissue distribution of the longer form of mouse SIRT3[J].Protein Sci,2009,18(3):514-525.
[8]HALLOWS WC,YU W,SMITH BC,et al.Sirt3 promotes the urea cycle and fatty acid oxidation during dietary restriction[J].Mol Cell,2011,41(2):139-149.
[9]PIRO S,ANELLO M,DI PIETRO C,et al.Chronic exposure to free fatty acids or high glucose induces apoptosis in rat pancreatic islets:possible role of oxidative stress[J].Metabolism,2002,51(10):1340-1347.
[10]SHI T,FAN GQ,XIAO SD.SIRT3 reduces lipid accumulation via AMPK activation in human hepatic cells[J].J Dig Dis,2010,11(1):55-62.
[11]HIRSCHEY MD,SHIMAZU T,GOETZMAN E,et al.SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation[J].Nature,2010,464(7285):121-125.
[12]WEIR HJ,MURRAY TK,KEHOE PG,et al.CNS SIRT3 expression is altered by reactive oxygen species and in Alzheimer's disease[J].PLoS One,2012,7(11):e48225.
[13]BELL EL,EMERLING BM,RICOULT SJ,et al.SirT3 suppresses hypoxia inducible factor 1 alpha and tumor growth by inhibiting mitochondrial ROS production[J].Oncogene,2011,30(26):2986-2996.
[14]JACOBS KM,PENNINGTON JD,BISHT KS,et al.SIRT3 interacts with the daf-16 homolog FOXO3a in the mitochondria,as well as increases FOXO3a dependent gene expression[J].Int J Biol Sci,2008,4(5):291-299.
[15]SOMEYA S,YU W,HALLOWS WC,et al.Sirt3 mediates reduction of oxidative damage and prevention of age-related hearing loss under caloric restriction[J].Cell,2010,143(5):802-812.
[16]YU W,GAO B,LI N,et al.Sirt3 deficiency exacerbates diabetic cardiac dysfunction:Role of Foxo3A-Parkin-mediated mitophagy[J].Biochim Biophys Acta Mol Basis Dis,2017,1863(8):1973-1983.
[17]SPRINGER MZ,MACLEOD KF.In Brief:Mitophagy:mechanisms and role in human disease[J].J Pathol,2016,240(3):253-255.
[18]FLIPPO KH,STRACK S.Mitochondrial dynamics in neuronal injury,development and plasticity[J].J Cell Sci,2017,130(4):671-681.
[19]LESCAI F,BLANCHE H,NEBEL A,et al.Human longevity and11p15.5:a study in 1321 centenarians[J].Eur J Hum Genet,2009,17(11):1515-1519.
[20]马祖亮.中国汉族人群STAT3基因多态性与肥胖及脂类代谢紊乱的关联研究[D].广州:南方医科大学,2014.
[21]BARRETT JC,HANSOUL S,NICOLAE DL,et al.Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease[J].Nat Genet,2008,40(8):955-962.
[22]谢庆云,魏萌,符培亮,等.信号传导和转录活化因子3基因单核苷酸多态性与中国汉族人类风湿关节炎的相关性[J].中国组织工程研究,2016,20(2):242-247.
[23]钟芳芳,蒋利萍,沈文婷,等.STAT3基因多态性与重庆地区汉族儿童川崎病易感性的关系[J].第三军医大学学报,2013,35(5):456-459.
[24]YIN X,PANG S,HUANG J,et al.Genetic and functional sequence variants of the SIRT3 gene promoter in myocardial infarction[J].PLoS One,2016,11(4):e153815.
[25]张爽.SIRT3与非酒精性脂肪性肝病的关联及功能研究[D].重庆:第三军医大学,2017.
[26]ALBANI D,PUPILLO E,BIANCHI E,et al.The role of single-nucleotide variants of the energy metabolism-linked genes SIRT3,PPARGC1A and APOE in amyotrophic lateral sclerosis risk[J].Genes Genet Syst,2017,91(6):301-309.
[27]KIM SH,LU HF,ALANO CC.Neuronal Sirt3 protects against excitotoxic injury in mouse cortical neuron culture[J].PLoS One,2011,6(3):e14731.
[28]张静怡,邓永宁,屈秋民.沉默信息调节因子3在神经退行性疾病中的作用[J].生命的化学,2015,35(3):377-382.
[29]SONG W,SONG Y,KINCAID B,et al.Mutant SOD1G93A triggers mitochondrial fragmentation in spinal cord motor neurons:neuroprotection by SIRT3 and PGC-1alpha[J].Neurobiol Dis,2013,51:72-81.
[30]YIN J,HAN P,SONG M,et al.Amyloid-beta increases tau by mediating Sirtuin3 in Alzheimer's disease[J].Mol Neurobiol,2018,55(11):8592-8601.
[31]ZHANG JY,DENG YN,ZHANG M,et al.SIRT3 acts as a neuroprotective agent in rotenone-induced Parkinson cell model[J].Neurochem Res,2016,41(7):1761-1773.
[32]ZARRABEITIA MT,VALERO C,MARTIN-ESCUDERO JC,et al.Association study of sirtuin 1 polymorphisms with bone mineral density and body mass index[J].Arch Med Res,2012,43(5):363-368.
[33]KALEMCI S,EDGUNLU TG,KARA M,et al.Sirtuin gene polymorphisms are associated with chronic obstructive pulmonary disease in patients in Mugla province[J].Kardiochir Torakochirurgia Pol,2014,11(3):306-310.
[34]FU J,JIN J,CICHEWICZ RH,et al.trans-(-)-epsilon-Viniferin increases mitochondrial sirtuin 3(SIRT3),activates AMP-activated protein kinase(AMPK),and protects cells in models of Huntington Disease[J].J Biol Chem,2012,287(29):24460-24472.
[35]YIN J,HAN P,TANG Z,et al.Sirtuin 3 mediates neuroprotection of ketones against ischemic stroke[J].J Cereb Blood Flow Metab,2015,35(11):1783-1789.
[36]DAI SH,CHEN T,LI X,et al.Sirt3 confers protection against neuronal ischemia by inducing autophagy:Involvement of the AMPK-mTOR pathway[J].Free Radic Biol Med,2017,108(8):345-353.
[37]PORTER GA,URCIUOLI WR,BROOKES PS,et al.SIRT3 deficiency exacerbates ischemia-reperfusion injury:implication for aged hearts[J].Am J Physiol Heart Circ Physiol,2014,306(12):H1602-H1609.
[2]VERDIN E,HIRSCHEY MD,FINLEY LW,et al.Sirtuin regulation of mitochondria:energy production,apoptosis,and signaling[J].Trends Biochem Sci,2010,35(12):669-675.
[3]AVALOS JL,CELIC I,MUHAMMAD S,et al.Structure of a Sir2 enzyme bound to an acetylated p53 peptide[J].Mol Cell,2002,10(3):523-535.
[4]JIN L,WEI W,JIANG Y,et al.Crystal structures of human SIRT3displaying substrate-induced conformational changes[J].J Biol Chem,2009,284(36):24394-24405.
[5]LOMBARD DB,ALT FW,CHENG HL,et al.Mammalian Sir2 homolog SIRT3 regulates global mitochondrial lysine acetylation[J].Mol Cell Biol,2007,27(24):8807-8814.
[6]IWAHARA T,BONASIO R,NARENDRA V,et al.SIRT3 functions in the nucleus in the control of stress-related gene expression[J].Mol Cell Biol,2012,32(24):5022-5034.
[7]JIN L,GALONEK H,ISRAELIAN K,et al.Biochemical characterization,localization,and tissue distribution of the longer form of mouse SIRT3[J].Protein Sci,2009,18(3):514-525.
[8]HALLOWS WC,YU W,SMITH BC,et al.Sirt3 promotes the urea cycle and fatty acid oxidation during dietary restriction[J].Mol Cell,2011,41(2):139-149.
[9]PIRO S,ANELLO M,DI PIETRO C,et al.Chronic exposure to free fatty acids or high glucose induces apoptosis in rat pancreatic islets:possible role of oxidative stress[J].Metabolism,2002,51(10):1340-1347.
[10]SHI T,FAN GQ,XIAO SD.SIRT3 reduces lipid accumulation via AMPK activation in human hepatic cells[J].J Dig Dis,2010,11(1):55-62.
[11]HIRSCHEY MD,SHIMAZU T,GOETZMAN E,et al.SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation[J].Nature,2010,464(7285):121-125.
[12]WEIR HJ,MURRAY TK,KEHOE PG,et al.CNS SIRT3 expression is altered by reactive oxygen species and in Alzheimer's disease[J].PLoS One,2012,7(11):e48225.
[13]BELL EL,EMERLING BM,RICOULT SJ,et al.SirT3 suppresses hypoxia inducible factor 1 alpha and tumor growth by inhibiting mitochondrial ROS production[J].Oncogene,2011,30(26):2986-2996.
[14]JACOBS KM,PENNINGTON JD,BISHT KS,et al.SIRT3 interacts with the daf-16 homolog FOXO3a in the mitochondria,as well as increases FOXO3a dependent gene expression[J].Int J Biol Sci,2008,4(5):291-299.
[15]SOMEYA S,YU W,HALLOWS WC,et al.Sirt3 mediates reduction of oxidative damage and prevention of age-related hearing loss under caloric restriction[J].Cell,2010,143(5):802-812.
[16]YU W,GAO B,LI N,et al.Sirt3 deficiency exacerbates diabetic cardiac dysfunction:Role of Foxo3A-Parkin-mediated mitophagy[J].Biochim Biophys Acta Mol Basis Dis,2017,1863(8):1973-1983.
[17]SPRINGER MZ,MACLEOD KF.In Brief:Mitophagy:mechanisms and role in human disease[J].J Pathol,2016,240(3):253-255.
[18]FLIPPO KH,STRACK S.Mitochondrial dynamics in neuronal injury,development and plasticity[J].J Cell Sci,2017,130(4):671-681.
[19]LESCAI F,BLANCHE H,NEBEL A,et al.Human longevity and11p15.5:a study in 1321 centenarians[J].Eur J Hum Genet,2009,17(11):1515-1519.
[20]马祖亮.中国汉族人群STAT3基因多态性与肥胖及脂类代谢紊乱的关联研究[D].广州:南方医科大学,2014.
[21]BARRETT JC,HANSOUL S,NICOLAE DL,et al.Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease[J].Nat Genet,2008,40(8):955-962.
[22]谢庆云,魏萌,符培亮,等.信号传导和转录活化因子3基因单核苷酸多态性与中国汉族人类风湿关节炎的相关性[J].中国组织工程研究,2016,20(2):242-247.
[23]钟芳芳,蒋利萍,沈文婷,等.STAT3基因多态性与重庆地区汉族儿童川崎病易感性的关系[J].第三军医大学学报,2013,35(5):456-459.
[24]YIN X,PANG S,HUANG J,et al.Genetic and functional sequence variants of the SIRT3 gene promoter in myocardial infarction[J].PLoS One,2016,11(4):e153815.
[25]张爽.SIRT3与非酒精性脂肪性肝病的关联及功能研究[D].重庆:第三军医大学,2017.
[26]ALBANI D,PUPILLO E,BIANCHI E,et al.The role of single-nucleotide variants of the energy metabolism-linked genes SIRT3,PPARGC1A and APOE in amyotrophic lateral sclerosis risk[J].Genes Genet Syst,2017,91(6):301-309.
[27]KIM SH,LU HF,ALANO CC.Neuronal Sirt3 protects against excitotoxic injury in mouse cortical neuron culture[J].PLoS One,2011,6(3):e14731.
[28]张静怡,邓永宁,屈秋民.沉默信息调节因子3在神经退行性疾病中的作用[J].生命的化学,2015,35(3):377-382.
[29]SONG W,SONG Y,KINCAID B,et al.Mutant SOD1G93A triggers mitochondrial fragmentation in spinal cord motor neurons:neuroprotection by SIRT3 and PGC-1alpha[J].Neurobiol Dis,2013,51:72-81.
[30]YIN J,HAN P,SONG M,et al.Amyloid-beta increases tau by mediating Sirtuin3 in Alzheimer's disease[J].Mol Neurobiol,2018,55(11):8592-8601.
[31]ZHANG JY,DENG YN,ZHANG M,et al.SIRT3 acts as a neuroprotective agent in rotenone-induced Parkinson cell model[J].Neurochem Res,2016,41(7):1761-1773.
[32]ZARRABEITIA MT,VALERO C,MARTIN-ESCUDERO JC,et al.Association study of sirtuin 1 polymorphisms with bone mineral density and body mass index[J].Arch Med Res,2012,43(5):363-368.
[33]KALEMCI S,EDGUNLU TG,KARA M,et al.Sirtuin gene polymorphisms are associated with chronic obstructive pulmonary disease in patients in Mugla province[J].Kardiochir Torakochirurgia Pol,2014,11(3):306-310.
[34]FU J,JIN J,CICHEWICZ RH,et al.trans-(-)-epsilon-Viniferin increases mitochondrial sirtuin 3(SIRT3),activates AMP-activated protein kinase(AMPK),and protects cells in models of Huntington Disease[J].J Biol Chem,2012,287(29):24460-24472.
[35]YIN J,HAN P,TANG Z,et al.Sirtuin 3 mediates neuroprotection of ketones against ischemic stroke[J].J Cereb Blood Flow Metab,2015,35(11):1783-1789.
[36]DAI SH,CHEN T,LI X,et al.Sirt3 confers protection against neuronal ischemia by inducing autophagy:Involvement of the AMPK-mTOR pathway[J].Free Radic Biol Med,2017,108(8):345-353.
[37]PORTER GA,URCIUOLI WR,BROOKES PS,et al.SIRT3 deficiency exacerbates ischemia-reperfusion injury:implication for aged hearts[J].Am J Physiol Heart Circ Physiol,2014,306(12):H1602-H1609.