您的位置：山东大学 -> 科技期刊社 -> 《山东大学学报（医学版）》

山东大学学报 (医学版) ›› 2020, Vol. 58 ›› Issue (8): 34-41.doi: 10.6040/j.issn.1671-7554.0.2020.0725

• 脑科学与类脑智能研究专题 • 上一篇    下一篇

线粒体与脑疾病

焉传祝*(),王伟,纪坤乾,赵玉英   

  1. 山东大学齐鲁医院神经内科，山东 济南 250012
  • 收稿日期:2020-05-01 出版日期:2020-08-07 发布日期:2020-08-07
  • 通讯作者: 焉传祝 E-mail:chuanzhuyan@163.com
  • 作者简介:焉传祝，医学博士，博士研究生导师，二级教授，泰山学者特聘专家。山东大学神经病学系主任，山东大学齐鲁医院副院长，青岛院区院长、脑科中心主任。主要研究方向为神经系统疑难罕见病，长期专注神经系统遗传变性疾病,神经肌肉、神经遗传代谢疾病,肌无力,肌萎缩,周围神经疾病以及神经免疫疾病的临床诊治和病理机制研究等。2013年成立山东大学神经肌肉与变性疾病研究所、山东省医药卫生神经系统罕见病重点实验室。目前储存冷冻神经肌肉活检标本和DNA标本5 000余例，涵盖近百种神经系统的疑难罕见病。在对国内脂质沉积性肌病的临床和病因研究中，发现了中国人脂质沉积性肌病对单用维生素B2治疗有肯定疗效，其病因是电子转运黄素蛋白脱氢酶(ETFDH)基因突变。该研究成果使全国近千例脂质沉积性肌病患者受益。在线粒体病、糖原累积病和炎症性肌病的临床诊治和病理机制研究领域也进行了较为深入的探索。承担国家自然科学基金项目4项，卫生部部属医院临床重点项目1项。共发表论文100余篇，其中在《Annals of Neurology》《Neurology》《Acta Neuropathologica》《J Neurol Neurosurg Psychiatry》《Stroke》《Lancet》《Clinical Picture》等国外期刊发表第一作者或通讯作者论文40余篇。主编著作2部，参编6部，获山东省科技进步二等奖2项，三等奖1项。目前任中华医学会神经病学分会副主任委员、神经肌肉病学组组长,山东省罕见病防治协会神经病罕见病分会主任委员, 《中华神经科杂志》副总编

Mitochondrial dysfunction and related brain diseases

Chuanzhu YAN*(),Wei WANG,Kunqian JI,Yuying ZHAO   

  1. Department of Neurology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong, China
  • Received:2020-05-01 Online:2020-08-07 Published:2020-08-07
  • Contact: Chuanzhu YAN E-mail:chuanzhuyan@163.com

RichHTML

17

PDF (PC)

669

摘要：

线粒体通过氧化磷酸化途径为机体提供大部分能量，并且参与细胞信号传导、炎症反应、细胞凋亡等多种生理生化过程。大脑对线粒体能量供应的变化十分敏感，线粒体功能障碍可通过多种途径的相互作用，参与遗传代谢性脑疾病、神经退行性脑疾病、精神心理脑疾病和脑老化等的发生发展过程。目前线粒体相关脑疾病尚缺乏特效治疗方案，线粒体的基因靶向治疗研究有望突破线粒体病的治疗瓶颈，为患者带去希望。

关键词: 线粒体脑病, 脑变性病, 精神心理疾病, 脑老化, 基因靶向治疗

Abstract:

Mitochondria provides most of the energy for the body through oxidative phosphorylation (OXPHOS) and participates in various physiological and biochemical processes such as cell signal transduction, inflammatory response and apoptosis. Brain is very sensitive to energy change. Mitochondrial dysfunction is associated with various disorders including genetic and metabolic diseases, neurodegenerative diseases, psychological diseases and brain aging via multiple pathways. At present, there is no specific treatment plan for mitochondrial encephalopathy. Research on mitochondrial gene targeted therapy is expected to break through the treatment bottleneck of mitochondrial diseases and brings hope to patients

Key words: Mitochondrial encephalopathy, Neurodegeneration, Psychological diseases, Brain aging, Targeted therapy

中图分类号: 

  • R742
1 Wiemerslage L , Lee D . Quantification of mitochondrial morphology in neurites of dopaminergic neurons using multiple parameters[J]. J Neurosci Methods, 2016, 262: 56- 65.
doi: 10.1016/j.jneumeth
2 Ernster L , Schatz G . Mitochondria: a historical review[J]. The Journal of Cell Biology, 1981, 91 (3 Pt 2): 227- 255.
3 Luft R , Ikkos D , Palmieri G , et al. A case of severe hypermetabolism of nonthyroid origin with a defect in the maintenance of mitochondrial respiratory control: a correlated clinical, biochemical, and morphological study[J]. J Clin Invest, 1962, 41: 1776- 804.
doi: 10.1172/JCI104637
4 Anderson S , Bankier AT , Barrell BG , et al. Sequence and organization of the human mitochondrial genome[J]. Nature, 1981, 290 (5806): 457- 465.
doi: 10.1038/290457a0
5 Holt IJ , Harding AE , Cooper JM , et al. Mitochondrial myopathies: clinical and biochemical features of 30 patients with major deletions of muscle mitochondrial DNA[J]. Ann Neurol, 1989, 26 (6): 699- 708.
doi: 10.1002/ana.410260603
6 Holt IJ , Harding AE , Morgan-Hughes JA . Deletions of muscle mitochondrial DNA in mitochondrial myopathies: sequence analysis and possible mechanisms[J]. Nucleic Acids Res, 1989, 17 (12): 4465- 4469.
doi: 10.1093/nar/17.12.4465
7 Bris C , Goudenege D , Desquiret-Dumas V , et al. Bioinformatics tools and databases to assess the pathogenicity of mitochondrial DNA variants in the field of next generation sequencing[J]. Front Genet, 2018, 9: 632.
doi: 10.3389/fgene.2018.00632
8 Luft R . The development of mitochondrial medicine[J]. P Natl Acad Sci Usa, 1994, 91 (19): 8731- 8738.
doi: 10.1073/pnas.91.19.8731
9 El-Hattab AW , Adesina AM , Jones J , et al. MELAS syndrome: Clinical manifestations, pathogenesis, and treatment options[J]. Mol Genet Metab, 2015, 116 (1-2): 4- 12.
doi: 10.1016/j.ymgme
10 Whitehead MT , Wien M , Lee B , et al. Black Toenail Sign in MELAS Syndrome[J]. Pediatr Neurol, 2017, 75: 61- 65.
doi: 10.1016/j.pediatrneurol.2017.06.017
11 El-Hattab AW , Emrick LT , Hsu JW , et al. Impaired nitric oxide production in children with MELAS syndrome and the effect of arginine and citrulline supplementation[J]. Mol Genet Metab, 2016, 117 (4): 407- 412.
doi: 10.1016/j.ymgme.2016.01.010
12 Goto Y , Nonaka I , Horai S . A mutation in the tRNA (Leu)(UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies[J]. Nature, 1990, 348 (6302): 651- 653.
doi: 10.1038/348651a0
13 Rodriguez MC , MacDonald JR , Mahoney DJ , et al. Beneficial effects of creatine, CoQ10, and lipoic acid in mitochondrial disorders[J]. Muscle Nerve, 2007, 35 (2): 235- 242.
14 Gerards M , Sallevelt SCEH , Smeets HJM . Leigh syndrome: Resolving the clinical and genetic heterogeneity paves the way for treatment options[J]. Mol Genet Metab, 2016, 117 (3): 300- 312.
doi: 10.1016/j.ymgme.2015.12.004
15 Bonfante E , Koenig MK , Adejumo RB , et al. The neuroimaging of Leigh syndrome: case series and review of the literature[J]. Pediatr Radiol, 2016, 46 (4): 443- 451.
doi: 10.1007/s00247-015-3523-5
16 Schubert Baldo M , Vilarinho L . Molecular basis of Leigh syndrome: a current look[J]. Orphanet J Rare Dis, 2020, 15 (1): 31.
doi: 10.1186/s13023-020-1297-9
17 Sofou K , De Coo IF , Isohanni P , et al. A multicenter study on Leigh syndrome: disease course and predictors of survival[J]. Orphanet J Rare Dis, 2014, 9: 52.
doi: 10.1186/1750-1172-9-52
18 Remes AM , Karppa M , Moilanen JS , et al. Epidemiology of the mitochondrial DNA 8344A>G mutation for the myoclonus epilepsy and ragged red fibres (MERRF) syndrome[J]. J Neurol Neurosur Ps, 2003, 74 (8): 1158- 1159.
doi: 10.1136/jnnp.74.8.1158
19 Finsterer J , Zarrouk-Mahjoub S , Shoffner JM . MERRF classification: Implications for diagnosis and clinical trials[J]. Pediatr Neurol, 2018, 80: 8- 23.
doi: 10.1016/j.pediatrneurol.2017.12.005
20 Juaristi L , Irigoyen C , Quiroga J . Neuropathy, ataxia, and retinitis pigmentosa syndrome: a multidisciplinary diagnosis[J]. Retin Cases Brief Rep, 2018.
doi: 10.1097/ICB.0000000000000835
21 Tatuch Y , Robinson BH . The mitochondrial DNA mutation at 8993 associated with NARP slows the rate of ATP synthesis in isolated lymphoblast mitochondria[J]. Biochem Bioph Res Co, 1993, 192 (1): 124- 128.
doi: 10.1006/bbrc.1993.1390
22 Claeys KG , Abicht A , Hausler M , et al. Novel genetic and neuropathological insights in neurogenic muscle weakness, ataxia, and retinitis pigmentosa (NARP)[J]. Muscle Nerve, 2016, 54 (2): 328- 333.
doi: 10.1002/mus.25125
23 Rahman S , Copeland WC . POLG-related disorders and their neurological manifestations[J]. Nat Rev Neurol, 2019, 15 (1): 40- 52.
24 Rose HR , Al Khalili Y . Alpers-Huttenlochen Syndrome (AHS, Alper Disease), In: StatPearls[M]. Treasure Island (FL): StatPearls Publishing, 2020.
25 Lane CA , Hardy J , Schott JM . Alzheimer's disease[J]. Eur J Neurol, 2018, 25 (1): 59- 70.
doi: 10.1111/ene.13439
26 Swerdlow RH . Mitochondria and mitochondrial cascades in Alzheimer's disease[J]. J Alzheimers Dis, 2018, 62 (3): 1403- 1416.
doi: 10.3233/JAD-170585
27 Terada T , Obi T , Bunai T , et al. In vivo mitochondrial and glycolytic impairments in patients with Alzheimer disease[J]. Neurology, 2020, 94 (15): 1592- 1604.
doi: 10.1212/WNL.0000000000009249
28 Agnihotri A , Aruoma OI . Alzheimer's disease and parkinson's disease: a nutritional toxicology perspective of the impact of oxidative stress, mitochondrial dysfunction, nutrigenomics and environmental chemicals[J]. J Am Coll Nutr, 2020, 39 (1): 16- 27.
doi: 10.1080/07315724.2019.1683379
29 Luque-Contreras D , Carvajal K , Toral-Rios D , et al. Oxidative stress and metabolic syndrome: cause or consequence of Alzheimer's disease?[J]. Oxid Med Cell Longev, 2014, 2014: 497802.
doi: 10.1155/2014/497802
30 Vila M , Przedborski S . Genetic clues to the pathogenesis of Parkinson's disease[J]. Nat Med, 2004, 10 (Suppl): 58- 62.
31 Pickrell AM , Youle RJ . The roles of PINK1, parkin, and mitochondrial fidelity in Parkinson's disease[J]. Neuron, 2015, 85 (2): 257- 273.
doi: 10.1016/j.neuron.2014.12.007
32 Krebiehl G , Ruckerbauer S , Burbulla LF , et al. Reduced basal autophagy and impaired mitochondrial dynamics due to loss of Parkinson's disease-associated protein DJ-1[J]. PLoS One, 2010, 5 (2): e9367.
doi: 10.1371/journal.pone.0009367
33 Repici M , Giorgini F . DJ-1 in Parkinson's disease: clinical insights and therapeutic perspectives[J]. J Clin Med, 2019, 8 (9): 1377.
doi: 10.3390/jcm8091377
34 Das NR , Sharma SS . Cognitive impairment associated with Parkinson's disease: role of mitochondria[J]. Curr Neuropharmacol, 2016, 14 (6): 584- 592.
doi: 10.2174/1570159X14666160104142349
35 Bates GP , Dorsey R , Gusella JF , et al. Huntington disease[J]. Nat Rev Dis Primers, 2015, 1: 15005.
doi: 10.1038/nrdp
36 Panov AV , Gutekunst CA , Leavitt BR , et al. Early mitochondrial calcium defects in Huntington's disease are a direct effect of polyglutamines[J]. Nat Neurosci, 2002, 5 (8): 731- 736.
doi: 10.1038/nn884
37 Di Cristo F , Finicelli M , Digilio FA , et al. Meldonium improves Huntington's disease mitochondrial dysfunction by restoring peroxisome proliferator-activated receptor gamma coactivator 1alpha expression[J]. J Cell Physiol, 2019, 234 (6): 9233- 9246.
doi: 10.1002/jcp.27602
38 Franco-Iborra S , Vila M , Perier C . Mitochondrial quality control in neurodegenerative diseases: focus on Parkinson's disease and Huntington's disease[J]. Front Neurosci, 2018, 12: 342.
doi: 10.3389/fnins.2018.00342
39 Orr AL , Li S , Wang CE , et al. N-terminal mutant huntingtin associates with mitochondria and impairs mitochondrial trafficking[J]. J Neurosci, 2008, 28 (11): 2783- 2792.
doi: 10.1523/JNEUROSCI.0106-08.2008
40 McColgan P , Tabrizi SJ . Huntington's disease: a clinical review[J]. Eur J Neurol, 2018, 25 (1): 24- 34.
doi: 10.1111/ene.13413
41 Holper L , Lan MJ , Brown PJ , et al. Brain cytochrome-c-oxidase as a marker of mitochondrial function: A pilot study in major depression using NIRS[J]. Depress Anxiety, 2019, 36 (8): 766- 779.
doi: 10.1002/da.22913
42 Kuffner K , Triebelhorn J , Meindl K , et al. Major Depressive Disorder is Associated with Impaired Mitochondrial Function in Skin Fibroblasts[J]. Cells, 2020, 9 (4): 884.
doi: 10.3390/cells9040884
43 Holper L , Ben-Shachar D , Mann JJ . Multivariate meta-analyses of mitochondrial complex I and IV in major depressive disorder, bipolar disorder, schizophrenia, Alzheimer disease, and Parkinson disease[J]. Neuropsychopharmacol, 2019, 44 (5): 837- 849.
doi: 10.1038/s41386-018-0090-0
44 Brown PJ , Brennan N , Ciarleglio A , et al. Declining skeletal muscle mitochondrial function associated with increased risk of depression in later life[J]. Am J Geriat Psychiat, 2019, 27 (9): 963- 971.
doi: 10.1016/j.jagp.2019.03.022
45 De Crescenzo F , Ciliberto M , Menghini D , et al. Is (18)F-FDG-PET suitable to predict clinical response to the treatment of geriatric depression? A systematic review of PET studies[J]. Aging Ment Health, 2017, 21 (9): 889- 894.
doi: 10.1080/13607863.2016.1247413
46 Stein DJ , Scott KM , de Jonge P , et al. Epidemiology of anxiety disorders: from surveys to nosology and back[J]. Dialogues Clin Neurosci, 2017, 19 (2): 127- 136.
47 Filiou MD , Sandi C . Anxiety and brain mitochondria: a bidirectional crosstalk[J]. Trends Neurosci, 2019, 42 (9): 573- 588.
doi: 10.1016/j.tins.2019.07.002
48 Misiewicz Z , Iurato S , Kulesskaya N , et al. Multi-omics analysis identifies mitochondrial pathways associated with anxiety-related behavior[J]. PLoS Genet, 2019, 15 (9): e1008358.
doi: 10.1371/journal.pgen.1008358
49 Papilloud A , Guillot de Suduiraut I , Zanoletti O , et al. Peripubertal stress increases play fighting at adolescence and modulates nucleus accumbens CB1 receptor expression and mitochondrial function in the amygdala[J]. Transl Psychiat, 2018, 8 (1): 156.
doi: 10.1038/s41398-018-0215-6
50 van der Kooij MA , Hollis F , Lozano L , et al. Diazepam actions in the VTA enhance social dominance and mitochondrial function in the nucleus accumbens by activation of dopamine D1 receptors[J]. Mol Psychiatr, 2018, 23 (3): 569- 578.
doi: 10.1038/mp.2017.135
51 Manivasagam T , Arunadevi S , Essa MM , et al. Role of oxidative stress and antioxidants in autism[J]. Adv Neurobiol, 2020, 24: 193- 206.
doi: 10.1007/978-3-030-30402-7_7
52 La Barbera L , Vedele F , Nobili A , et al. Neurodevelopmental disorders: functional role of ambra1 in autism and schizophrenia[J]. Mol Neurobiol, 2019, 56 (10): 6716- 6724.
doi: 10.1007/s12035-019-1557-7
53 Schwede M , Nagpal S , Gandal MJ , et al. Strong correlation of downregulated genes related to synaptic transmission and mitochondria in post-mortem autism cerebral cortex[J]. J Neurodev Disord, 2018, 10 (1): 18.
doi: 10.1186/s11689-018-9237-x
54 Carrasco M , Salazar C , Tiznado W , et al. Alterations of mitochondrial biology in the oral mucosa of Chilean children with autism spectrum disorder (ASD)[J]. Cells, 2019, 8 (4): 367.
doi: 10.3390/cells8040367
55 Pomatto LCD , Davies KJA . Adaptive homeostasis and the free radical theory of ageing[J]. Free Radical Bio Med, 2018, 124: 420- 430.
doi: 10.1016/j.freeradbiomed
56 Cardoso S , Correia S , Carvalho C , et al. Perspectives on mitochondrial uncoupling proteins-mediated neuroprotection[J]. J Bioenerg Biomembr, 2015, 47 (1-2): 119- 131.
doi: 10.1007/s10863-014-9580-x
57 Haas RH . Mitochondrial dysfunction in aging and diseases of aging[J]. Biology (Basel), 2019, 8 (2): 48.
doi: 10.3390/biology8020048
58 Kandlur A , Satyamoorthy K , Gangadharan G . Oxidative stress in cognitive and epigenetic aging: a retrospective glance[J]. Front Mol Neurosci, 2020, 13: 41.
doi: 10.3389/fnmol.2020.00041
59 Grimm A , Eckert A . Brain aging and neurodegeneration: from a mitochondrial point of view[J]. J Neurochem, 2017, 143 (4): 418- 431.
doi: 10.1111/jnc.14037
60 Yao SQ , Liew SS , Qin X , et al. Smart design of nanomaterials for mitochondria-targeted nanotherapeutics[J]. Angew Chem Int Ed Engl, 2020.
doi: 10.1002/anie.201915826
61 Yasuzaki Y , Yamada Y , Ishikawa T , et al. Validation of mitochondrial gene delivery in liver and skeletal muscle via hydrodynamic injection using an artificial mitochondrial reporter dna vector[J]. Mol Pharmaceut, 2015, 12 (12): 4311- 4320.
doi: 10.1021/acs.molpharmaceut.5b00511
62 Cardoso AM , Morais CM , Cruz AR , et al. Gemini surfactants mediate efficient mitochondrial gene delivery and expression[J]. Mol Pharmaceut, 2015, 12 (3): 716- 730.
doi: 10.1021/mp5005349
63 Yamada Y , Fukuda Y , Harashima H . An analysis of membrane fusion between mitochondrial double membranes and MITO-Porter, mitochondrial fusogenic vesicles[J]. Mitochondrion, 2015, 24: 50- 55.
doi: 10.1016/j.mito.2015.07.003
64 Yamada Y , Ishikawa T , Harashima H . Validation of the use of an artificial mitochondrial reporter DNA vector containing a Cytomegalovirus promoter for mitochondrial transgene expression[J]. Biomaterials, 2017, 136: 56- 66.
doi: 10.1016/j.biomaterials
65 Chuah JA , Matsugami A , Hayashi F , et al. Self-assembled peptide-based system for mitochondrial-targeted gene delivery: functional and structural insights[J]. Biomacromolecules, 2016, 17 (11): 3547- 3557.
doi: 10.1021/acs.biomac.6b01056
66 Gammage PA , Viscomi C , Simard ML , et al. Genome editing in mitochondria corrects a pathogenic mtDNA mutation in vivo[J]. Nat Med, 2018, 24 (11): 1691- 1695.
doi: 10.1038/s41591-018-0165-9
67 Bacman SR , Kauppila JHK , Pereira CV , et al. MitoTALEN reduces mutant mtDNA load and restores tRNA(Ala) levels in a mouse model of heteroplasmic mtDNA mutation[J]. Nat Med, 2018, 24 (11): 1696- 1700.
doi: 10.1038/s41591-018-0166-8
68 Jang YH , Lim KI . Recent advances in mitochondria-targeted gene delivery[J]. Molecules (Basel, Switzerland), 2018, 23 (9): 2316.
doi: 10.3390/molecules23092316
[1] 白洁,刘玥,张宁宁,温洋,彭芸,程华. 中枢神经肿瘤样脱髓鞘病2例[J]. 山东大学学报 (医学版), 2020, 58(9): 103-105.
Viewed
Full text


Abstract

Cited
  Shared   
  Discussed   
[1] 索东阳,申飞,郭皓,刘力畅,杨惠敏,杨向东. Tim-3在药物性急性肾损伤动物模型中的表达及作用机制[J]. 山东大学学报 (医学版), 2020, 58(7): 1 -6 .
[2] 张宝文,雷香丽,李瑾娜,罗湘俊,邹容. miR-21-5p靶向调控TIMP3抑制2型糖尿病肾病小鼠肾脏系膜细胞增殖及细胞外基质堆积[J]. 山东大学学报 (医学版), 2020, 58(7): 7 -14 .
[3] 龙婷婷,谢明,周璐,朱俊德. Noggin蛋白对小鼠脑缺血再灌注损伤后学习和记忆能力与齿状回结构的影响[J]. 山东大学学报 (医学版), 2020, 58(7): 15 -23 .
[4] 付洁琦,张曼,张晓璐,李卉,陈红. Toll样受体4抑制过氧化物酶体增殖物激活受体γ加重血脂蓄积的分子机制[J]. 山东大学学报 (医学版), 2020, 58(7): 24 -31 .
[5] 马青源,蒲沛东,韩飞,王超,朱洲均,王维山,史晨辉. miR-27b-3p调控SMAD1对骨肉瘤细胞增殖、迁移和侵袭作用的影响[J]. 山东大学学报 (医学版), 2020, 58(7): 32 -37 .
[6] 李宁,李娟,谢艳,李培龙,王允山,杜鲁涛,王传新. 长链非编码RNA AL109955.1在80例结直肠癌组织中的表达及对细胞增殖与迁移侵袭的影响[J]. 山东大学学报 (医学版), 2020, 58(7): 38 -46 .
[7] 史爽,李娟,米琦,王允山,杜鲁涛,王传新. 胃癌miRNAs预后风险评分模型的构建与应用[J]. 山东大学学报 (医学版), 2020, 58(7): 47 -52 .
[8] 肖娟,肖强,丛伟,李婷,丁守銮,张媛,邵纯纯,吴梅,刘佳宁,贾红英. 两种甲状腺超声数据报告系统诊断效能的比较[J]. 山东大学学报 (医学版), 2020, 58(7): 53 -59 .
[9] 丁祥云,于清梅,张文芳,庄园,郝晶. 胰岛素样生长因子II在84例多囊卵巢综合征患者颗粒细胞中的表达和促排卵结局的相关性[J]. 山东大学学报 (医学版), 2020, 58(7): 60 -66 .
[10] 徐玉香,刘煜东,张蓬,段瑞生. 101例脑小血管病患者脑微出血危险因素的回顾性分析[J]. 山东大学学报 (医学版), 2020, 58(7): 67 -71 .
版权所有 © 2018 《山东大学学报(医学版)》编辑部　
地址:山东大学科技期刊社（济南市历城区山大南路27号山东大学中心校区明德楼B座721室） 电话: 0531-88366918 E-mail: xbyxb@sdu.edu.cn
本系统由北京玛格泰克科技发展有限公司设计开发