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中华临床医师杂志(电子版) ›› 2024, Vol. 18 ›› Issue (02) : 223 -230. doi: 10.3877/cma.j.issn.1674-0785.2024.02.019

综述

线粒体相关内质网膜相关线粒体功能障碍在阿尔茨海默病中的研究进展
于伟伟1, 张国高2, 吴军2, 胡俊2, 黄一宁3, 徐晶4,†()   
  1. 1. 518055　深圳，南方科技大学化学系与格拉布斯研究院　广东省催化化学重点实验室　深圳市小分子药物发现和合成重点实验室;518036　深圳，北京大学深圳医院神经内科
    2. 518036　深圳，北京大学深圳医院神经内科
    3. 100034　北京，北京大学第一医院神经内科
    4. 518055　深圳，南方科技大学化学系与格拉布斯研究院　广东省催化化学重点实验室　深圳市小分子药物发现和合成重点实验室
  • 收稿日期:2023-11-20 出版日期:2024-02-15
  • 通信作者: 徐晶

Role of mitochondrial dysfunction associated with mitochondria-associated endoplasmic reticulum membranes in Alzheimer's disease

Weiwei Yu1, Guogao Zhang2, Jun Wu2, Jun Hu2, Yining Huang3, Jing Xu4,†()   

  1. 1. Department of Chemistry and Shenzhen Grubbs Institute, Guangdong Provincial Key Laboratory of Catalysis, Shenzhen Key Laboratory of Small Molecule Drug Discovery and Synthesis, Southern University of Science and Technology, Shenzhen 518055, China;Department of Neurology, Peking University Shenzhen Hospital, Shenzhen 518036, China
    2. Department of Neurology, Peking University Shenzhen Hospital, Shenzhen 518036, China
    3. Department of Neurology, Peking University First Hospital, Beijing 100034, China
    4. Department of Chemistry and Shenzhen Grubbs Institute, Guangdong Provincial Key Laboratory of Catalysis, Shenzhen Key Laboratory of Small Molecule Drug Discovery and Synthesis, Southern University of Science and Technology, Shenzhen 518055, China
  • Received:2023-11-20 Published:2024-02-15
  • Corresponding author: Jing Xu
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引用本文：

于伟伟, 张国高, 吴军, 胡俊, 黄一宁, 徐晶. 线粒体相关内质网膜相关线粒体功能障碍在阿尔茨海默病中的研究进展[J]. 中华临床医师杂志(电子版), 2024, 18(02): 223-230.

Weiwei Yu, Guogao Zhang, Jun Wu, Jun Hu, Yining Huang, Jing Xu. Role of mitochondrial dysfunction associated with mitochondria-associated endoplasmic reticulum membranes in Alzheimer's disease[J]. Chinese Journal of Clinicians(Electronic Edition), 2024, 18(02): 223-230.

阿尔茨海默病（AD）是一种进行性神经退行性疾病，临床主要表现为认知功能下降和行为损害，给家庭和社会带来沉重的经济负担。近年来研究发现，线粒体相关内质网膜（MAM）与AD早期病理性改变存在显著相关性，其中包括常见的线粒体功能障碍，即MAM上调可引起细胞内线粒体功能紊乱和结构变化，主要包括线粒体Aβ沉积、线粒体动力学改变和线粒体自噬，进而导致线粒体功能障碍，促进AD发生。本文就MAM介导的线粒体功能障碍在AD病理进程中的作用及机制研究进展进行综述，为早期AD治疗并延缓AD进程提供新的潜在靶点。

关键词: 阿尔茨海默病, 线粒体相关内质网膜, 线粒体Aβ, 线粒体动力学, 线粒体自噬

Alzheimer's disease (AD) is a progressive neurodegenerative disease with clinical manifestations of cognitive dysfunction and behavioral impairment, imposing a heavy economic burden on families and society. Recent studies have revealed that mitochondria-associated endoplasmic reticulum membranes (MAM) have a significant correlation with early pathological changes of AD, such as mitochondrial dysfunction. MAM up-regulation can lead to intracellular mitochondrial dysfunction and structural changes, mainly including mitochondrial Aβ deposition, mitochondrial dynamics alternations, and mitochondrial autophagy, thus promoting the occurrence of AD. This article reviews the role of MAM-mediated mitochondrial dysfunction in the pathological changes of AD, providing new potential targets for the early treatment of AD and the delay of AD progression.

Key words: Alzheimer's disease, Mitochondria-associated endoplasmic reticulum membranes, Mitochondrial Aβ, Mitochondrial dynamics, Mitochondrial autophagy
图1 AD中MAM介导的线粒体Aβ沉积对线粒体功能的影响。图a为MAM产生的Aβ蛋白通过TOM/TIM复合物转运至线粒体内；图b为线粒体Aβ通过与ABAD相互作用抑制乙酰辅酶A及COX活性，减少线粒体ATP产生；图c为线粒体Aβ可直接抑制COX活性；图d为线粒体Aβ促进CypD引起的mPTP开放，导致线粒体功能障碍，ATP减少，ROS升高 注：AD为阿尔茨海默病；MAM为线粒体相关内质网膜；APP为β淀粉样前体蛋白；Aβ为β淀粉样蛋白；TOM为外膜转运酶；TIM为内膜转运酶；mPTP为线粒体通透性转换孔；CypD为亲环素D；Cox为细胞色素C氧化酶；ABAD为Aβ结合乙醇脱氢酶；NAD为烟酰胺腺嘌呤二核苷酸；FAD为黄素腺嘌呤二核苷酸
图2 AD中MAM介导的线粒体动力学对线粒体功能的影响。图a为正常神经元中的线粒体融合和分裂处于动态平衡，且线粒体形态大小均一，并均匀的分布在细胞质内；图b为AD影响神经元中的线粒体倾向于分裂，故线粒体形态大小不均一，且重新成簇分布在核周，并通过不同机制影响线粒体功能 注：AD为阿尔茨海默病；MAM为线粒体相关内质网膜；Mito为线粒体；ER为内质网；MFN2为线粒体融合蛋白2；OPA1为视神经萎缩蛋白1；DLP1为动力相关蛋白1；FIS1为线粒体裂变蛋白
图3 AD中MAM介导的线粒体自噬缺陷。图a为泛素依赖性途径。PINK与Pakin结合可泛素化并降解OMM蛋白，并将受损的线粒体选择出来与溶酶体结合，从而完成线粒体自噬过程，但AD阻断了该线粒体自噬途径的启动；图b为受体依赖性途径。运动和缺氧可激活MAM蛋白FUNDC1，并通过其LIR结构域与LC3结合，促进线粒体自噬，而FUNDC1是否参与到AD中线粒体自噬缺陷仍待研究 注：AD为阿尔茨海默病；ER为内质网；MAM为线粒体相关内质网膜；Mito为线粒体；PINK为假定激酶；TOM为外膜转运酶；TIM为内膜转运酶；CK2为肌酸激酶2；ULK为UNC-51样激酶1；FUNDC1为FUN14结构域1
1
Weller J, Budson A. Current understanding of Alzheimer's disease diagnosis and treatment[J]. F1000Res, 2018, 7.
2
Lauer AA, Grimm HS, Apel B, et al. Mechanistic link between vitamin B12 and Alzheimer's disease[J]. Biomolecules, 2022, 12(1).
3
GBD 2019 Dementia Forecasting Collaborators. Estimation of the global prevalence of dementia in 2019 and forecasted prevalence in 2050: an analysis for the Global Burden of Disease Study 2019[J]. Lancet Public Health, 2022, 7(2): e105-e125.
4
Jia L, Du Y, Chu L, et al. Prevalence, risk factors, and management of dementia and mild cognitive impairment in adults aged 60 years or older in China: a cross-sectional study[J]. Lancet Public Health, 2020, 5(12): e661-e671.
5
李嘉辰, 刘献增. 经颅磁刺激在阿尔茨海默病诊断及治疗中的研究进展[J/OL]. 中华临床医师杂志(电子版), 2021, 15(4): 308-312.
6
Cummings J, Lee G, Ritter A, et al. Alzheimer's disease drug development pipeline: 2020[J]. Alzheimers Dement (N Y), 2020, 6(1): e12050.
7
Alzheimer A, Stelzmann RA, Schnitzlein HN, et al. An English translation of Alzheimer's 1907 paper, "Uber eine eigenartige Erkankung der Hirnrinde"[J]. Clin Anat, 1995, 8(6): 429-431.
8
Yao J, Irwin RW, Zhao L, et al. Mitochondrial bioenergetic deficit precedes Alzheimer's pathology in female mouse model of Alzheimer's disease[J]. Proc Natl Acad Sci U S A, 2009, 106(34): 14670-14675.
9
巩凤超, 毕胜. 阿尔茨海默病的线粒体损伤致病机制研究新进展[J/OL]. 中华临床医师杂志(电子版), 2011, 5(18): 5419-5422.
10
Jellinger KA. Neuropathology of the Alzheimer's continuum: an update[J]. Free Neuropathol, 2020, 1.
11
Bae H, Shim KH, Yoo J, et al. Double mutations in a patient with early-onset Alzheimer's disease in Korea: An APP Val551Met and a PSEN2 His169Asn[J]. Int J Mol Sci, 2023, 24(8).
12
Goedert M, Spillantini MG. A century of Alzheimer's disease[J]. Science, 2006, 314(5800): 777-781.
13
Frisoni GB, Altomare D, Thal DR, et al. The probabilistic model of Alzheimer disease: the amyloid hypothesis revised[J]. Nat Rev Neurosci, 2022, 23(1): 53-66.
14
Levitis E, Vogel JW, Funck T, et al. Differentiating amyloid beta spread in autosomal dominant and sporadic Alzheimer's disease[J]. Brain Commun, 2022, 4(3): fcac085.
15
Bennett RE, DeVos SL, Dujardin S, et al. Enhanced Tau aggregation in the presence of amyloid β[J]. Am J Pathol, 2017, 187(7): 1601-1612.
16
Rinaldi A. Setbacks and promises for drugs against Alzheimer's disease: As pharmaceutical companies are retreating from drug development for Alzheimer's, new approaches are being tested in academia and biotech companies[J]. EMBO Rep, 2018, 19(9).
17
Lane CA, Hardy J, Schott JM. Alzheimer's disease[J]. Eur J Neurol, 2018, 25(1): 59-70.
18
Zhang H, Bezprozvanny I. "Dirty dancing" of calcium and autophagy in Alzheimer's disease[J]. Life (Basel), 2023, 13(5).
19
Stefani M, Liguri G. Cholesterol in Alzheimer's disease: unresolved questions[J]. Curr Alzheimer Res, 2009, 6(1): 15-29.
20
Tassone G, Kola A, Valensin D, et al. Dynamic interplay between copper toxicity and mitochondrial dysfunction in Alzheimer's disease[J]. Life (Basel), 2021, 11(5).
21
Yu W, Jin H, Huang Y. Mitochondria-associated membranes (MAMs): a potential therapeutic target for treating Alzheimer's disease[J]. Clin Sci (Lond), 2021, 135(1): 109-126.
22
Friedman JR, Lackner LL, West M, et al. ER tubules mark sites of mitochondrial division[J]. Science, 2011, 334(6054): 358-362.
23
Poston CN, Krishnan SC, Bazemore-Walker CR. In-depth proteomic analysis of mammalian mitochondria-associated membranes (MAM)[J]. J Proteomics, 2013, 79: 219-230.
24
Zhao J, Li J, Li G, et al. The role of mitochondria-associated membranes mediated ROS on NLRP3 inflammasome in cardiovascular diseases[J]. Front Cardiovasc Med, 2022, 9: 1059576.
25
Gabaldón T, Pittis AA. Origin and evolution of metabolic sub-cellular compartmentalization in eukaryotes[J]. Biochimie, 2015, 119: 262-268.
26
Bhattacharyya R, Black SE, Lotlikar MS, et al. Axonal generation of amyloid-β from palmitoylated APP in mitochondria-associated endoplasmic reticulum membranes[J]. Cell Rep, 2021, 35(7): 109134.
27
Area-Gomez E, Schon EA. Mitochondria-associated ER membranes and Alzheimer disease[J]. Curr Opin Genet Dev, 2016, 38: 90-96.
28
Zhu X, Perry G, Smith MA, et al. Abnormal mitochondrial dynamics in the pathogenesis of Alzheimer's disease[J]. J Alzheimers Dis, 2013, 33Suppl 1(01): S253-262.
29
Wertkin AM, Turner RS, Pleasure SJ, et al. Human neurons derived from a teratocarcinoma cell line express solely the 695-amino acid amyloid precursor protein and produce intracellular beta-amyloid or A4 peptides[J]. Proc Natl Acad Sci U S A, 1993, 90(20): 9513-9517.
30
Capetillo-Zarate E, Gracia L, Tampellini D, et al. Intraneuronal Aβ accumulation, amyloid plaques, and synapse pathology in Alzheimer's disease[J]. Neurodegener Dis, 2012, 10(1-4): 56-59.
31
Takahashi RH, Nagao T, Gouras GK. Plaque formation and the intraneuronal accumulation of β-amyloid in Alzheimer's disease[J]. Pathol Int, 2017, 67(4): 185-193.
32
Varte V, Munkelwitz JW, Rincon-Limas DE. Insights from Drosophila on Aβ- and tau-induced mitochondrial dysfunction: mechanisms and tools[J]. Front Neurosci, 2023, 17: 1184080.
33
Caspersen C, Wang N, Yao J, et al. Mitochondrial Abeta: a potential focal point for neuronal metabolic dysfunction in Alzheimer's disease[J]. FASEB J, 2005, 19(14): 2040-2041.
34
Dragicevic N, Mamcarz M, Zhu Y, et al. Mitochondrial amyloid-beta levels are associated with the extent of mitochondrial dysfunction in different brain regions and the degree of cognitive impairment in Alzheimer's transgenic mice[J]. J Alzheimers Dis, 2010, 20Suppl 2: S535-550.
35
Devi L, Prabhu BM, Galati DF, et al. Accumulation of amyloid precursor protein in the mitochondrial import channels of human Alzheimer's disease brain is associated with mitochondrial dysfunction[J]. J Neurosci, 2006, 26(35): 9057-9068.
36
Janikiewicz J, Szymański J, Malinska D, et al. Mitochondria-associated membranes in aging and senescence: structure, function, and dynamics[J]. Cell Death Dis, 2018, 9(3): 332.
37
Schreiner B, Hedskog L, Wiehager B, et al. Amyloid-β peptides are generated in mitochondria-associated endoplasmic reticulum membranes[J]. J Alzheimers Dis, 2015, 43(2): 369-374.
38
Hu W, Wang Z, Zheng H. Mitochondrial accumulation of amyloid β (Aβ) peptides requires TOMM22 as a main Aβ receptor in yeast[J]. J Biol Chem, 2018, 293(33): 12681-12689.
39
Du Yan S, Zhu Y, Stern ED, et al. Amyloid beta -peptide-binding alcohol dehydrogenase is a component of the cellular response to nutritional stress[J]. J Biol Chem, 2000, 275(35): 27100-27109.
40
He XY, Dobkin C, Brown WT, et al. 3-Hydroxyacyl-CoA and alcohol dehydrogenase activities of mitochondrial type 10 17β-hydroxysteroid dehydrogenase in neurodegeneration study[J]. J Alzheimers Dis, 2022, 88(4): 1487-1497.
41
Morsy A, Maddeboina K, Gao J, et al. Functionalized allopurinols targeting amyloid-binding alcohol dehydrogenase rescue Aβ-induced mitochondrial dysfunction[J]. ACS Chem Neurosci, 2022, 13(14): 2176-2190.
42
Morsy A, Trippier PC. Amyloid-binding alcohol dehydrogenase (ABAD) inhibitors for the treatment of Alzheimer's disease[J]. J Med Chem, 2019, 62(9): 4252-4264.
43
Patro S, Ratna S, Yamamoto HA, et al. ATP Synthase and mitochondrial bioenergetics dysfunction in Alzheimer's disease[J]. Int J Mol Sci, 2021, 22(20).
44
Cottrell DA, Borthwick GM, Johnson MA, et al. The role of cytochrome c oxidase deficient hippocampal neurones in Alzheimer's disease[J]. Neuropathol Appl Neurobiol, 2002, 28(5): 390-396.
45
Parks RJ, Menazza S, Holmström KM, et al. Cyclophilin D-mediated regulation of the permeability transition pore is altered in mice lacking the mitochondrial calcium uniporter[J]. Cardiovasc Res, 2019, 115(2): 385-394.
46
Du H, Guo L, Fang F, et al. Cyclophilin D deficiency attenuates mitochondrial and neuronal perturbation and ameliorates learning and memory in Alzheimer's disease[J]. Nat Med, 2008, 14(10): 1097-1105.
47
Mohamed Asik R, Suganthy N, Aarifa MA, et al. Alzheimer's disease: A molecular view of β-Amyloid induced morbific events[J]. Biomedicines, 2021, 9(9).
48
Cohen MM, Tareste D. recent insights into the structure and function of Mitofusins in mitochondrial fusion[J]. F1000Res, 2018, 7.
49
Ainbinder A, Boncompagni S, Protasi F, et al. Role of Mitofusin-2 in mitochondrial localization and calcium uptake in skeletal muscle[J]. Cell Calcium, 2015, 57(1): 14-24.
50
Basso V, Marchesan E, Peggion C, et al. Regulation of ER-mitochondria contacts by Parkin via Mfn2[J]. Pharmacol Res, 2018, 138: 43-56.
51
Kandimalla R, Reddy PH. Multiple faces of dynamin-related protein 1 and its role in Alzheimer's disease pathogenesis[J]. Biochim Biophys Acta, 2016, 1862(4): 814-828.
52
Wu S, Lu Q, Wang Q, et al. Binding of FUN14 Domain containing 1 with inositol 1,4,5-Trisphosphate receptor in mitochondria-associated endoplasmic reticulum membranes maintains mitochondrial dynamics and function in hearts in vivo[J]. Circulation, 2017, 136(23): 2248-2266.
53
Wang X, Su B, Siedlak SL, 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.
54
Bertholet AM, Delerue T, Millet AM, et al. Mitochondrial fusion/fission dynamics in neurodegeneration and neuronal plasticity[J]. Neurobiol Dis, 2016, 90: 3-19.
55
Krishnan KJ, Ratnaike TE, De Gruyter HL, et al. Mitochondrial DNA deletions cause the biochemical defect observed in Alzheimer's disease[J]. Neurobiol Aging, 2012, 33(9): 2210-2214.
56
Coskun PE, Beal MF, Wallace DC. Alzheimer's brains harbor somatic mtDNA control-region mutations that suppress mitochondrial transcription and replication[J]. Proc Natl Acad Sci U S A, 2004, 101(29): 10726-10731.
57
Weaver D, Eisner V, Liu X, et al. Distribution and apoptotic function of outer membrane proteins depend on mitochondrial fusion[J]. Mol Cell, 2014, 54(5): 870-878.
58
Anzell AR, Maizy R, Przyklenk K, et al. Mitochondrial quality Control and Disease: Insights into Ischemia-Reperfusion Injury[J]. Mol Neurobiol, 2018, 55(3): 2547-2564.
59
Pickles S, Vigié P, Youle RJ. Mitophagy and quality control mechanisms in mitochondrial maintenance[J]. Curr Biol, 2018, 28(4): R170-R185.
60
Reddy PH, Oliver DM. Amyloid beta and phosphorylated Tau-induced defective autophagy and mitophagy in Alzheimer's disease[J]. Cells, 2019, 8(5).
61
Chakravorty A, Jetto CT, Manjithaya R. Dysfunctional mitochondria and mitophagy as drivers of Alzheimer's disease pathogenesis[J]. Front Aging Neurosci, 2019, 11: 311.
62
Wang DK, Zheng HL, Zhou WS, et al. Mitochondrial dysfunction in oxidative stress-mediated intervertebral disc degeneration[J]. Orthop Surg, 2022, 14(8): 1569-1582.
63
Koyano F, Okatsu K, Kosako H, et al. Ubiquitin is phosphorylated by PINK1 to activate parkin[J]. Nature 2014, 510(7503): 162-166.
64
Chan NC, Salazar AM, Pham AH, et al. Broad activation of the ubiquitin-proteasome system by Parkin is critical for mitophagy[J]. Hum Mol Genet, 2011, 20(9): 1726-1737.
65
Mao H, Chen W, Chen L, et al. Potential role of mitochondria-associated endoplasmic reticulum membrane proteins in diseases[J]. Biochem Pharmacol, 2022, 199: 115011.
66
Mary A, Eysert F, Checler F, et al. Mitophagy in Alzheimer's disease: molecular defects and therapeutic approaches[J]. Mol Psychiatry, 2023, 28(1): 202-216.
67
Chen M, Chen Z, Wang Y, et al. Mitophagy receptor FUNDC1 regulates mitochondrial dynamics and mitophagy[J]. Autophagy, 2016, 12(4): 689-702.
68
Wu H, Xue D, Chen G, et al. The BCL2L1 and PGAM5 axis defines hypoxia-induced receptor-mediated mitophagy[J]. Autophagy, 2014, 10(10): 1712-1725.
69
Zhang W, Siraj S, Zhang R, et al. Mitophagy receptor FUNDC1 regulates mitochondrial homeostasis and protects the heart from I/R injury[J]. Autophagy, 2017, 13(6): 1080-1081.
70
Wu W, Lin C, Wu K, et al. FUNDC1 regulates mitochondrial dynamics at the ER-mitochondrial contact site under hypoxic conditions[J]. EMBO J, 2016, 35(13): 1368-1384.
71
Wu W, Tian W, Hu Z, et al. ULK1 translocates to mitochondria and phosphorylates FUNDC1 to regulate mitophagy[J]. EMBO Rep, 2014, 15(5): 566-575.
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