Research progress in cell and animal models of Leber hereditary optic neuropathy_Chinese Journal of Ocular Fundus Diseases

Authors：

Yang Xueying ,  Chen Changzheng

Department of Ophthalmology, Renmin Hospital of Wuhan University, Wuhan 430060, China;

Corresponding author：

Chen Changzheng, Email: whuchenchzh@163.com

Keywords：

Mitochondrial diseases; DNA, mitochondrial; Disease models, animal; Review

DOI：

10.3760/cma.j.cn511434-20210207-00073

Video：

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Abstract Full text Figures/Tables Video References Cited by

Leber hereditary optic neuropathy (LHON) is a blinding disease caused by mutations in mitochondrial DNA. It is a classic disease model for studying mitochondrial abnormalities. Its main mutation sites are m11778G.A, m.3460G.A and m.14484T.C. LHON cell models are mainly produced by lymphoblasts, fibroblasts, cell hybrids and induced pluripotent stem cells, while LHON animal models are mainly mice, which are produced by rotenone and ND4 mutants. Although the research on the LHON model has achieved good results, there are still many difficulties in constructing an ideal experimental model, which severely limit the exploring to the pathogenesis and therapeutic drugs of LHON. A detailed understanding of the application and characteristics of existing models in LHON will help improve experimental design and construct new models.

Citation： Yang Xueying, Chen Changzheng. Research progress in cell and animal models of Leber hereditary optic neuropathy. Chinese Journal of Ocular Fundus Diseases, 2021, 37(10): 825-830. doi: 10.3760/cma.j.cn511434-20210207-00073 Copy

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2. Jankauskaitė E, Bartnik E, Kodroń A. Investigating Leber's hereditary optic neuropathy: cell models and future perspectives[J]. Mitochondrion, 2017, 32: 19-26. DOI: 10.1016/j.mito.2016.11.006.
3. Giordano L, Deceglie S, d'Adamo P, et al. Cigarette toxicity triggers Leber's hereditary optic neuropathy by affecting mtDNA copy number, oxidative phosphorylation and ROS detoxification pathways[J/OL]. Cell Death Dis, 2015, 6(12): e2021[2015-12-17].https://pubmed.ncbi.nlm.nih.gov/26673666/. DOI: 10.1038/cddis.2015.364.
4. Caporali L, Maresca A, Capristo M, et al. Incomplete penetrance in mitochondrial optic neuropathies[J]. Mitochondrion, 2017, 36: 130-137. DOI: 10.1016/j.mito.2017.07.004.
5. 杨硕, 刘磊, 裴晗, 等. 腺相关病毒2-ND4基因转染细胞线粒体的研究[J]. 中华实验眼科杂志, 2014, 32(8): 693-695. DOI: 10.3760/cma.j.issn.2096-0160.2014.08.005.Yang S, Liu L, Pei H, et al. Study on transfection of adeno associated virus 2-ND4 gene into mitochondria[J]. Chin J Exp Ophthalmol, 2014, 32(8): 693-695. DOI: 10.3760/cma.j.issn.2096-0160.2014.08.005.
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10. Chen C, Chen Y, Guan MX. A peep into mitochondrial disorder: multifaceted from mitochondrial DNA mutations to nuclear gene modulation[J]. Protein Cell, 2015, 6(12): 862-870. DOI: 10.1007/s13238-015-0175-z.
11. Jiang P, Jin X, Peng Y, et al. The exome sequencing identified the mutation in YARS2 encoding the mitochondrial tyrosyl-tRNA synthetase as a nuclear modifier for the phenotypic manifestation of Leber's hereditary optic neuropathy-associated mitochondrial DNA mutation[J]. Hum Mol Genet, 2016, 25(3): 584-596. DOI: 10.1093/hmg/ddv498.
12. Jankauskaitė E, Ambroziak AM, Hajieva P, et al. Testosterone increases apoptotic cell death and decreases mitophagy in Leber's hereditary optic neuropathy cells[J]. J Appl Genet, 2020, 61(2): 195-203. DOI: 10.1007/s13353-020-00550-y.
13. Toritsuka M, Makinodan M, Yamauchi T, et al. Altered gene expression in lymphoblastoid cell lines after subculture[J]. In Vitro Cell Dev Biol Anim, 2018, 54(7): 523-527. DOI: 10.1007/s11626-018-0267-1.
14. Pereira SP, Deus CM, Serafim TL, et al. Metabolic and phenotypic characterization of human skin fibroblasts after forcing oxidative capacity[J]. Toxicol Sci, 2018, 164(1): 191-204. DOI: 10.1093/toxsci/kfy068.
15. Tun AW, Chaiyarit S, Kaewsutthi S, et al. Profiling the mitochondrial proteome of Leber's hereditary optic neuropathy (LHON) in Thailand: down-regulation of bioenergetics and mitochondrial protein quality control pathways in fibroblasts with the 11778G>A mutation[J/OL]. PLoS One, 2014, 9(9): e106779[2014-09-12].https://pubmed.ncbi.nlm.nih.gov/25215595/. DOI: 10.1371/journal.pone.0106779.
16. Zhou L, Chan JCY, Chupin S, et al. Increased protein S-glutathionylation in Leber's hereditary optic neuropathy (LHON)[J/OL]. Int J Mol Sci, 2020, 21(8): 3027[2020-04-24]. https://pubmed.ncbi.nlm.nih.gov/32344771/. DOI: 10.3390/ijms21083027.
17. Uittenbogaard M, Brantner CA, Fang Z, et al. The m. 11778 A>G variant associated with the coexistence of Leber's hereditary optic neuropathy and multiple sclerosis-like illness dysregulates the metabolic interplay between mitochondrial oxidative phosphorylation and glycolysis[J]. Mitochondrion, 2019, 46: 187-194. DOI: 10.1016/j.mito.2018.06.001.
18. Catarino CB, Ahting U, Gusic M, et al. Characterization of a Leber's hereditary optic neuropathy (LHON) family harboring two primary LHON mutations m. 11778G>A and m. 14484T>C of the mitochondrial DNA[J]. Mitochondrion, 2017, 36: 15-20. DOI: 10.1016/j.mito.2016.10.002.
19. Yu-Wai-Man P, Soiferman D, Moore DG, et al. Evaluating the therapeutic potential of idebenone and related quinone analogues in Leber hereditary optic neuropathy[J]. Mitochondrion, 2017, 36: 36-42. DOI: 10.1016/j.mito.2017.01.004.
20. Chao de la Barca JM, Simard G, Amati-Bonneau P, et al. The metabolomic signature of Leber's hereditary optic neuropathy reveals endoplasmic reticulum stress[J]. Brain, 2016, 139(11): 2864-2876. DOI: 10.1093/brain/aww222.
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22. Bacman SR, Nissanka N, Moraes CT. Cybrid technology[J]. Methods Cell Biol, 2020, 155: 415-439. DOI: 10.1016/bs.mcb.2019.11.025.
23. Wilkins HM, Carl SM, Swerdlow RH. Cytoplasmic hybrid (cybrid) cell lines as a practical model for mitochondriopathies[J]. Redox Biol, 2014, 2: 619-631. DOI: 10.1016/j.redox.2014.03.006.
24. Ji Y, Zhang J, Yu J, et al. Contribution of mitochondrial ND13394T>C mutation to the phenotypic manifestation of Leber's hereditary optic neuropathy[J]. Hum Mol Genet, 2019, 28(9): 1515-1529. DOI: 10.1093/hmg/ddy450.
25. Zhang J, Jiang P, Jin X, et al. Leber's hereditary optic neuropathy caused by the homoplasmic ND1m. 3635G>A mutation in nine Han Chinese families[J]. Mitochondrion, 2014, 18: 18-26. DOI: 10.1016/j.mito.2014.08.008.
26. Zhang J, Ji Y, Lu Y, et al. Leber's hereditary optic neuropathy (LHON)-associated ND5 12338T >C mutation altered the assembly and function of complex Ⅰ, apoptosis and mitophagy[J]. Hum Mol Genet, 2018, 27(11): 1999-2011. DOI: 10.1093/hmg/ddy107.
27. Ji Y, Zhang J, Lu Y, et al. Complex Ⅰ mutations synergize to worsen the phenotypic expression of Leber's hereditary optic neuropathy[J]. J Biol Chem, 2020, 295(38): 13224-13238. DOI: 10.1074/jbc.RA120.014603.
28. Sharma LK, Tiwari M, Rai NK, et al. Mitophagy activation repairs Leber's hereditary optic neuropathy-associated mitochondrial dysfunction and improves cell survival[J]. Hum Mol Genet, 2019, 28(3): 422-433. DOI: 10.1093/hmg/ddy354.
29. Zhang J, Ji Y, Liu X, et al. Leber's hereditary optic neuropathy caused by a mutation in mitochondrial tRNA(Thr) in eight Chinese pedigrees[J]. Mitochondrion, 2018, 42: 84-91. DOI: 10.1016/j.mito.2017.12.003.
30. Hudson G, Carelli V, Spruijt L, et al. Clinical expression of Leber hereditary optic neuropathy is affected by the mitochondrial DNA-haplogroup background[J]. Am J Hum Genet, 2007, 81(2): 228-233. DOI: 10.1086/519394.
31. Caporali L, Iommarini L, La Morgia C, et al. Peculiar combinations of individually non-pathogenic missense mitochondrial DNA variants cause low penetrance Leber's hereditary optic neuropathy[J/OL]. PLoS Genet, 2018, 14(2): e1007210[2018-02-14].https://pubmed.ncbi.nlm.nih.gov/29444077/. DOI: 10.1371/journal.pgen.1007210.
32. López-Gallardo E, Emperador S, Hernández-Ainsa C, et al. Food derived respiratory complex Ⅰinhibitors modify the effect of Leber hereditary optic neuropathy mutations[J]. Food Chem Toxicol, 2018, 120: 89-97. DOI: 10.1016/j.fct.2018.07.014.
33. Datta S, Baudouin C, Brignole-Baudouin F, et al. The eye drop preservative benzalkonium chloride potently induces mitochondrial dysfunction and preferentially affects LHON mutant cells[J]. Invest Ophthalmol Vis Sci, 2017, 58(4): 2406-2412. DOI: 10.1167/iovs.16-20903.
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Research progress of optical coherence tomography and optical coherence tomography angiography in Leber hereditary optic neuropathy

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Research progress in cell and animal models of Leber hereditary optic neuropathy

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