[1]王祯莲,宋国强.Drp1相关线粒体异常与阿尔茨海默病的研究进展[J].常州大学学报(自然科学版),2020,32(02):74-79.[doi:10.3969/j.issn.2095-0411.2020.02.010]
 WANG Zhenlian,SONG Guoqiang.Increased Mitochondrial Fission in the Pathogenesis of Alzheimer's Disease[J].Journal of Changzhou University(Natural Science Edition),2020,32(02):74-79.[doi:10.3969/j.issn.2095-0411.2020.02.010]
点击复制

Drp1相关线粒体异常与阿尔茨海默病的研究进展()
分享到:

常州大学学报(自然科学版)[ISSN:2095-0411/CN:32-1822/N]

卷:
第32卷
期数:
2020年02期
页码:
74-79
栏目:
生物医学工程
出版日期:
2020-03-28

文章信息/Info

Title:
Increased Mitochondrial Fission in the Pathogenesis of Alzheimer's Disease
文章编号:
2095-0411(2020)02-0074-06
作者:
王祯莲宋国强
(常州大学 制药与生命科学学院,江苏 常州 213164 )
Author(s):
WANG Zhenlian SONG Guoqiang
(School of Pharmaceutical Engineering & Life Sciences, Changzhou University, Changzhou 213164,China)
关键词:
线粒体过度分裂 阿尔茨海默病 Drp1
Keywords:
increased mitochondrial fission Alzheimer's disease Drp1
分类号:
TK 8
DOI:
10.3969/j.issn.2095-0411.2020.02.010
文献标志码:
A
摘要:
线粒体动力学异常是阿尔茨海默病(AD)发病过程中的早期事件。 β-淀粉样蛋白(Aβ)引起线粒体分裂增加,融合减少,导致线粒体功能障碍和神经元损伤。动力学相关蛋白1(Drp1)是调控线粒体过度分裂的关键分子。理解AD发病过程中线粒体过度分裂的机制有利于为研究以Drp1为靶点治疗AD提供理论和实验依据。
Abstract:
Abnormal mitochondrial dynamics is an early event in Alzheimer's disease. Aβ, in associ-ation with mitochondria, causes excessive mitochondrial fission and reduced mitochondrial fusion, leading to mitochondrial dysfunction and neuronal damage in AD-affected neurons. Increased mitochondrial fission is a key factor in mitochondrial dysfunction, probably caused by mutant protein(s)interacting with Drp1, resulting in the initiation of abnormal mitochondrial fission. Understanding the mechanism of excessive mitochondrial fission in the pathogenesis of AD is beneficial for providing a theoretical and experimental basis in the study of Drp1 as a target treatment of AD.

参考文献/References:

[1]HARDY J, ALLSOP D. Amyloid deposition as the central event in the aetiology of Alzheimer's disease[J]. Trends Pharmacol Sci, 1991, 12(10):383-388.
[2]SELKOE D J, HARDY J. The amyloid hypothesis of Alzheimer's disease at 25 years[J]. EMBO Mol Med, 2016, 8(6):595-608.
[3]WANG Y J. Alzheimer disease: lessons from immunotherapy for Alzheimer disease[J]. Nat Rev Neurol, 2014, 10(4):188-189.
[4]SWERDLOW R H, KHAN S M. A “mitochondrial cascade hypothesis” for sporadic Alzheimer's disease[J]. Med Hypotheses, 2004, 63(1):8-20.
[5]WANG X, WANG W, LI L, et al. Oxidative stress and mitochondrial dysfunction in Alzheimer's disease[J]. Biochim Biophys Acta, 2014, 1842(8):1240-1247.
[6]CHA M Y, HAN S H, SON S M, et al. Mitochondria-specific accumulation of amyloid beta induces mitochondrial dysfunction leading to apoptotic cell death[J]. PLoS One, 2012, 7(4):e34929.
[7]PAGANI L, ECKERT A. Amyloid-Beta interaction with mitochondria[J]. Int J Alzheimers Dis, 2011, 2011:925050.
[8]LAFERLA F M, GREEN K N, ODDO S. Intracellular amyloid-beta in Alzheimer's disease[J]. Nat Rev Neurosci, 2007, 8(7):499-509.
[9]WALSH D M, SELKOE D J. A beta oligomers-a decade of discovery[J]. J Neurochem, 2007, 101(5):1172-1184.
[10]DETMER S A, CHAN D C. Functions and dysfunctions of mitochondrial dynamics[J]. Nat Rev Mol Cell Biol, 2007, 8(11):870-879.
[11]LEE Y J, JEONG S Y, KARBOWSKI M, et al. Roles of the mammalian mitochondrial fission and fusion mediators Fis1, Drp1, and Opa1 in apoptosis[J]. Mol Biol Cell, 2004, 15(11):5001-5011.
[12]WANG X, SU B, LEE H G, et al. Impaired balance of mitochondrial fission and fusion in Alzheimer's disease[J]. J Neurosci, 2009, 29(28):9090-9103.
[13]MANCZAK M, MAO P, CALKINS M J, et al. Mitochondria-targeted antioxidants protect against amyloid-beta toxicity in Alzheimer's disease neurons[J]. J Alzheimers Dis, 2010, 20(Suppl 2):S609-631.
[14]MANCZAK M, CALKINS M J, REDDY P H. Impaired mitochondrial dynamics and abnormal interaction of amyloid beta with mitochondrial protein Drp1 in neurons from patients with Alzheimer's disease: implications for neuronal damage[J]. Hum Mol Genet, 2011, 20(13):2495-2509.
[15]CALKINS M J, MANCZAK M, MAO P, et al. Impaired mitochondrial biogenesis, defective axonal transport of mitochondria, abnormal mitochondrial dynamics and synaptic degeneration in a mouse model of Alzheimer's disease[J]. Hum Mol Genet, 2011, 20(23):4515-4529.
[16]TRUSHINA E, NEMUTLU E, ZHANG S, et al. Defects in mitochondrial dynamics and metabolomic signatures of evolving energetic stress in mouse models of familial Alzheimer's disease[J]. PLoS One, 2012, 7(2):e32737.
[17]SILVA D F, SELFRIDGE J E, LU J, et al. Bioenergetic flux, mitochondrial mass and mitochondrial morphology dynamics in AD and MCI cybrid cell lines[J]. Hum Mol Genet, 2013, 22(19):3931-3946.
[18]CHO D H, NAKAMURA T, FANG J, et al. S-nitrosylation of Drp1 mediates beta-amyloid-related mitochondrial fission and neuronal injury[J]. Science, 2009, 324(5923):102-105.
[19]REDDY P H, TRIPATHI R, TROUNG Q, et al. Abnormal mitochondrial dynamics and synaptic degeneration as early events in Alzheimer's disease: implications to mitochondria-targeted antioxidant therapeutics[J]. Biochim Biophys Acta, 2012, 1822(5):639-649.
[20]ZHU X, PERRY G, SMITH M A, et al. Abnormal mitochondrial dynamics in the pathogenesis of Alzheimer's disease[J]. J Alzheimers Dis, 2013, 33(Suppl 1):S253-262.
[21]WANG X, SU B, SIEDLAK S L, et al. Amyloid-beta overproduction causes abnormal mitochondrial dynamics via differential modulation of mitochondrial fission/fusion proteins[J]. Proc Natl Acad Sci U S A, 2008, 105(49):19318-19323.
[22]REDDY P H. Amyloid beta, mitochondrial structural and functional dynamics in Alzheimer's disease[J]. Exp Neurol, 2009, 218(2):286-292.
[23]CALKINS M J, REDDY P H. Amyloid beta impairs mitochondrial anterograde transport and degenerates synapses in Alzheimer's disease neurons[J]. Biochim Biophys Acta, 2011, 1812(4):507-513.
[24]WANG X, PERRY G, SMITH M A, et al. Amyloid-beta-derived diffusible ligands cause impaired axonal transport of mitochondria in neurons[J]. Neurodegener Dis, 2010, 7(1/2/3):56-59.
[25]DU H, GUO L, YAN S, et al. Early deficits in synaptic mitochondria in an Alzheimer's disease mouse model[J]. Proc Natl Acad Sci U S A, 2010, 107(43):18670-18675.
[26]REDDY P H, REDDY T P, MANCZAK M, et al. Dynamin-related protein 1 and mitochondrial fragmentation in neurodegenerative diseases[J]. Brain Res Rev, 2011, 67(1/2):103-118.
[27]KANDIMALLA R, REDDY P H. Multiple faces of dynamin-related protein 1 and its role in Alzheimer's disease pathogenesis[J]. Biochim Biophys Acta, 2016, 1862(4):814-828.
[28]WANG W, YIN J, MA X, et al. Inhibition of mitochondrial fragmentation protects against Alzheimer's disease in rodent model[J]. Hum Mol Genet, 2017, 26(21):4118-4131.
[29]YU T, ROBOTHAM J L, YOON Y. Increased production of reactive oxygen species in hyperglycemic conditions requires dynamic change of mitochondrial morphology[J]. Proc Natl Acad Sci U S A, 2006, 103(8):2653-2658.
[30]MANCZAK M, REDDY P H. Abnormal interaction between the mitochondrial fission protein Drp1 and hyperphosphorylated tau in Alzheimer's disease neurons: implications for mitochondrial dysfunction and neuronal damage[J]. Hum Mol Genet, 2012, 21(11):2538-2547.
[31]BOSSY B, PETRILLI A, KLINGLMAYR E, et al. S-Nitrosylation of DRP1 does not affect enzymatic activity and is not specific to Alzheimer's disease[J]. J Alzheimers Dis, 2010, 20(Suppl 2):S513-526.
[32]YAN J, LIU X H, HAN M Z, et al. Blockage of GSK3beta-mediated Drp1 phosphorylation provides neuroprotection in neuronal and mouse models of Alzheimer's disease[J]. Neurobiol Aging, 2015, 36(1):211-227.
[33]GUO M Y, SHANG L, HU Y Y, et al. The role of Cdk5-mediated Drp1 phosphorylation in Abeta1-42 induced mitochondrial fission and neuronal apoptosis[J]. J Cell Biochem, 2018, 119(6):4815-4825.
[34]ZHOU L, ZHANG Q, ZHANG P, et al. C-Abl-mediated Drp1 phosphorylation promotes oxidative stress-induced mitochondrial fragmentation and neuronal cell death[J]. Cell Death Dis, 2017, 8(10):e3117.
[35]ZHANG L, TRUSHIN S, CHRISTENSEN T A, et al. Altered brain energetics induces mitochondrial fission arrest in Alzheimer's Disease[J]. Sci Rep, 2016, 6:18725.
[36]TAGUCHI N, ISHIHARA N, JOFUKU A, et al. Mitotic phosphorylation of dynamin-related GTPase Drp1 participates in mitochondrial fission[J]. J Biol Chem, 2007, 282(15):11521-11529.
[37]ZAJA I, BAI X, LIU Y, et al. Cdk1, PKCdelta and calcineurin-mediated Drp1 pathway contributes to mitochondrial fission-induced cardiomyocyte death[J]. Biochem Biophys Res Commun, 2014, 453(4):710-721.
[38]KASHATUS J A, NASCIMENTO A, MYERS L J, et al. Erk2 phosphorylation of Drp1 promotes mitochondrial fission and MAPK-driven tumor growth[J]. Mol Cell, 2015, 57(3):537-551.
[39]CHO B, CHO H M, KIM H J, et al. CDK5-dependent inhibitory phosphorylation of Drp1 during neuronal maturation[J]. Exp Mol Med, 2014, 46:e105.
[40]KIM B, PARK J, CHANG K T, et al. Peroxiredoxin 5 prevents amyloid-beta oligomer-induced neuronal cell death by inhibiting ERK-Drp1-mediated mitochondrial fragmentation[J]. Free Radic Biol Med, 2016, 90:184-194.
[41]KIM D I, LEE K H, GABR A A, et al. Abeta-induced Drp1 phosphorylation through Akt activation promotes excessive mitochondrial fission leading to neuronal apoptosis[J]. Biochim Biophys Acta, 2016, 1863(11):2820-2834.

备注/Memo

备注/Memo:
收稿日期:2019-01-21。
基金项目:国家自然科学基金资助项目(81201657)。
作者简介:王祯莲(1980—),女,山西阳泉人,硕士,讲师。E-mail:wangzhenlian@cczu.edu.cn
更新日期/Last Update: 2020-04-28