БИОХИМИЯ, 2022, том 87, вып. 8, с. 1014–1029

УДК 616-092.18

Влияние Тау‑белка на функции митохондрий

Обзор

© 2022 Х.Х. Епремян *7700077@mail.ru, Т.Н. Голева, Р.А. Звягильская

ФИЦ «Биотехнологии» РАН, 119071 Москва, Россия

Поступила в редакцию 27.04.2022
После доработки 04.07.2022
Принята к публикации 06.07.2022

DOI: 10.31857/S0320972522080036

КЛЮЧЕВЫЕ СЛОВА: болезнь Альцгеймера, Тау-белок, биоэнергетика, митохондрии.

Аннотация

Болезнь Альцгеймера является наиболее распространенным возрастным прогрессирующим нейродегенеративным заболеванием коры головного мозга и гиппокампа, приводящим к когнитивным нарушениям. Принято считать, что накопление неправильно свернутых и агрегированных белков, Aβ‑амилоидных сенильных бляшек и гиперфосфорилированного белка Тау является основным признаком заболевания. Внутриклеточные последствия болезни Альцгеймера характеризуются митохондриальной дисфункцией, окислительным стрессом, ЭПР-стрессом, нарушением аутофагии, серьезными метаболическими проблемами, приводящими к массивному апоптозу нейронов. То, что митохондрии являются ключевым звеном во всех этих процессах, легло в основу так называемой «гипотезы митохондриального каскада». В обзоре представлены современные данные о молекулярных механизмах развития болезни Альцгеймера, связанных с митохондриями. Особое внимание уделено взаимодействию Тау-белка с митохондриями, а также перспективным терапевтическим подходам, направленным на ослабление или предотвращение развития нейродегенерации.

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* Адресат для корреспонденции.

Вклад авторов

Х.Х. Епремян, Р.А. Звягильская – концепция и руководство работой; Х.Х. Епремян – написание текста; Р.А. Звягильская, Т.Н. Голева – редактирование текста статьи.

Финансирование

Работа выполнена при частичной поддержке Российского фонда фундаментальных исследований (грант № 19-34-90165).

Конфликт интересов

Авторы заявляют об отсутствии конфликта интересов.

Соблюдение этических норм

Настоящая статья не содержит описания каких-либо исследований с участием людей или животных в качестве объектов, проведённых кем-либо из авторов.

Список литературы

1. Goleva, T., Rogov, A., and Zvyagilskaya, R. (2017) Alzheimer’s disease: molecular hall marks and yeast models, J. Alzheimer’s Dis. Parkinsonism, 7, 394-401, doi: 10.4172/2161-0460.1000394.

2. Soria Lopez, J. A., González, H. M., and Léger, G. C. (2019) Alzheimer’s disease, Handb. Clin. Neurol., 167, 231-255, doi: 10.1016/B978-0-12-804766-8.00013-3.

3. Eckert, A., Nisbet, R., Grimm, A., and Götz, J. (2014) March separate, strike together – role of phosphorylated TAU in mitochondrial dysfunction in Alzheimer’s disease, Biochim. Biophys. Acta, 1842, 1258-1266, doi: 10.1016/j.bbadis.2013.08.013.

4. Manczak, M., and Reddy, P. H. (2012) Abnormal interaction between the mitochondrial fission protein Drp1 and hyperphosphorylated tau in Alzheimer’s disease neurons: implications for mitochondrial dysfunction and neuronal damage, Hum. Mol. Genet., 21, 2538-2547, doi: 10.1093/hmg/dds072.

5. Rai, S. N., Singh, C., Singh, A., Singh, M. P., and Singh, B. K. (2020) Mitochondrial dysfunction: a potential therapeutic target to treat Alzheimer’s disease, Mol. Neurobiol., 57, 3075-3088, doi: 10.1007/s12035-020-01945-y.

6. John, A., and Reddy, P. H. (2021) Synaptic basis of Alzheimer’s disease: focus on synaptic amyloid beta, P-tau and mitochondria, Ageing Res. Rev., 65, 101208, doi: 10.1016/j.arr.2020.101208.

7. Briston, T., and Hicks, A. R. (2018) Mitochondrial dysfunction and neurodegenerative proteinopathies: mechanisms and prospects for therapeutic intervention, Biochem Soc Trans., 46, 829-842, doi: 10.1042/BST20180025.

8. Amadoro, G., Corsetti, V., Stringaro, A., Colone, M., D’Aguanno, S., et al. (2010) A NH2 tau fragment targets neuronal mitochondria at AD synapses: possible implications for neurodegeneration, J. Alzheimer’s Dis., 21, 445-470, doi: 10.3233/JAD-2010-100120.

9. David, D.C., Hauptmann, S., Scherping, I., Schuessel, K., Keil, U., et al. (2005) Proteomic and functional analyses reveal a mitochondrial dysfunction in P301L tau transgenic mice, J. Biol. Chem., 280, 23802-23814, doi: 10.1074/jbc.M500356200.

10. Rhein, V., Song, X., Wiesner, A., Ittner, L. M., Baysang, G., et al. (2009) Amyloid-b and tau synergistically impair the oxidative phosphorylation system in triple transgenic Alzheimer’s disease mice, Proc. Natl. Acad. Sci. USA, 106, 20057-20062, doi: 10.1073/pnas.0905529106.

11. Zhu, H., Zhang, W., Zhao, Y., Shu, X., Wang, W., et al. (2018) GSK3β-mediated tau hyperphosphorylation triggers diabetic retinal neurodegeneration by disrupting synaptic and mitochondrial functions, Mol. Neurodegener., 13, 62, doi: 10.1186/s13024-018-0295-z.

12. DuBoff, B., Feany, M., and Götz, J. (2013) Why size matters – balancing mitochondrial dynamics in Alzheimer’s disease, Trends Neurosci., 36, 325-335, doi: 10.1016/j.tins.2013.03.002.

13. Li, X.C., Hu, Y., Wang, Z., Luo, Y., Zhang, Y., et al. (2016) Human wild-type full-length tau accumulation disrupts mitochondrial dynamics and the functions via increasing mitofusins, Sci. Rep., 6, 24756, doi: 10.1038/srep24756.

14. Pérez, M. J., Vergara-Pulgar, K., Jara, C., Cabezas-Opazo, F., and Quintanilla, R. A. (2018) Caspase-cleaved tau impairs mitochondrial dynamics in Alzheimer’s disease, Mol. Neurobiol., 55, 1-15, doi: 10.1007/s12035-017-0385-x.

15. Lopes, S., Teplytska, L., Vaz-Silva, J., Dioli, C., Trindade, R., et al. (2017) Tau deletion prevents stress-induced dendritic atrophy in prefrontal cortex: role of synaptic mitochondria, Cereb. Cortex, 27, 2580-2591, doi: 10.1093/cercor/bhw057.

16. Vossel, K. A., Zhang, K., Brodbeck, J., Daub, A. C., Sharma, P., et al. (2010) Tau reduction prevents Abeta-induced defects in axonal transport, Science, 330, 198, doi: 10.1126/science.1194653.

17. Yao, J., Irwin, R. W., Zhao, L., Nilsen, J., Hamilton, R. T., et al. (2009) Mitochondrial bioenergetic deficit precedes Alzheimer’s pathology in female mouse model of Alzheimer’s disease, Proc. Natl. Acad. Sci. USA, 106, 14670-14675, doi: 10.1073/pnas.0903563106.

18. Resende, R., Moreira, P. I., Proenca, T., Deshpande, A., Busciglio, J., et al. (2008) Brain oxidative stress in a triple-transgenic mouse model of Alzheimer disease, Free Radic. Biol. Med., 44, 2051-2057, doi: 10.1016/j.freeradbiomed.2008.03.012.

19. Sensi, S. L., Rapposelli, I. G., Frazzini, V., and Mascetra, N. (2008) Altered oxidant-mediated intraneuronal zinc mobilization in a triple transgenic mouse model of Alzheimer’s disease, Exp. Gerontol., 43, 488-492, doi: 10.1016/j.exger.2007.10.018.

20. Chou, J. L., Shenoy, D. V., Thomas, N., Choudhary, P. K., Laferla, F. M., et al. (2011) Early dysregulation of the mitochondrial proteome in a mouse model of Alzheimer’s disease, J. Proteom., 74, 466-479, doi: 10.1016/j.jprot.2010.12.012.

21. Kandimalla, R., Manczak, M., Fry, D., Suneetha, Y., Sesaki, H., et al. (2016) Reduced dynamin-related protein 1 protects against phosphorylated Tau-induced mitochondrial dysfunction and synaptic damage in Alzheimer’s disease, Hum. Mol. Genet., 25, 4881-4897, doi: 10.1093/hmg/ddw312.

22. Reddy, P. H., and Oliver, D. M. (2019) Amyloid beta and phosphorylated tau-induced defective autophagy and mitophagy in Alzheimer’s disease, Cells, 8, doi: 10.3390/cells8050488.

23. Medala, V.K., Gollapelli, B., Dewanjee, S., Ogunmokun, G., Kandimalla, R., et al. (2021) Mitochondrial dysfunction, mitophagy, and role of dynamin-related protein 1 in Alzheimer’s disease, J. Neurosci. Res., 99, 1120-1135, doi: 10.1002/jnr.24781.

24. Fuente-Muñoz, C. E., Rosas-Lemus, M., Moreno-Castilla, P., Bermúdez-Rattoni, F., Uribe-Carvajal, S., et al. (2020) Age-dependent decline in synaptic mitochondrial function is exacerbated in vulnerable brain regions of female 3xTg-AD mice, Int. J. Mol. Sci., 21, 8727, doi: 10.3390/ijms21228727.

25. Shefa, U., Jeong, N. Y., Song, I. O., Chung, H. J., Kim, D., et al. (2019) Mitophagy links oxidative stress conditions and neurodegenerative diseases, Neural Regen. Res., 14, 749-756, doi: 10.4103/1673-5374.249218.

26. Morton, H., Kshirsagar, S., Orlov, E., Bunquin, L. E., Sawant, N., et al. (2021) Defective mitophagy and synaptic degeneration in Alzheimer’s disease: focus on aging, mitochondria and synapse, Free Radic. Biol. Med., 172, 652-667, doi: 10.1016/j.freeradbiomed.2021.07.013.

27. Reiss, A. B., Arain, H. A., Stecker, M. M., Siegart, N. M., and Kasselman, L. J. (2018) Amyloid toxicity in Alzheimer’s disease, Rev. Neurosci., 29, 613-627, doi: 10.1515/revneuro-2017-0063.

28. Camilleri, A., Ghio, S., Caruana, M., Weckbecker, D., Schmidt, F., et al. (2020) Tau-induced mitochondrial membrane perturbation is dependent upon cardiolipin, Biochim. Biophys. Acta Biomembr., 1862, 183064, doi: 10.1016/j.bbamem.2019.183064.

29. Tang, Z., Ioja, E., Bereczki, E., Hultenby, K., Li, C., et al. (2015) mTor mediates tau localization and secretion: implication for Alzheimer’s disease, Biochim. Biophys. Acta, 1853, 1646-1657, doi: 10.1016/j.bbamcr.2015.03.003.

30. Amorim, J. A., Canas, P. M., Tome, A. R., Rolo, A. P., Agostinho, P., et al. (2017) Mitochondria in excitatory and inhibitory synapses have similar susceptibility to amyloid-beta peptides modeling Alzheimer’s disease, J. Alzheimer’s Dis., 60, 525-536, doi: 10.3233/JAD-170356.

31. Camilleri, A., Zarb, C., Caruana, M., Ostermeier, U., Ghio, S., et al. (2013) Mitochondrial membrane perermeabilization by amyloid aggregates and protection by polyphenols, Biochim. Biophys. Acta, 1828, 2532-2543, doi: 10.1016/j.bbamem.2013.06.026.

32. Ardail, D., Privat, J. P., Egret-Charlier, M., Levrat, C., Lerme, F., et al. (1990) Mitochondrial contact sites. Lipid composition and dynamics, J. Biol. Chem., 265, 18797-18802.

33. Paradies, G., Paradies, V., De Benedictis, V., Ruggiero, F. M., and Petrosillo, G. (2014) Functional role of cardiolipin in mitochondrial bioenergetics, Biochim. Biophys. Acta, 1837, 408-417, doi: 10.1016/j.bbabio.2013.10.006.

34. Suga, K., Hamasaki, A., Chinzaka, J., and Umakoshi, H. (2016) Liposomes modified with cardiolipin can act as a platform to regulate the potential flux of NADP+-dependent isocitrate dehydrogenase, Metab. Eng. Commun., 3, 8-14, doi: 10.1016/j.meteno.2015.11.002.

35. Schug, Z. T., and Gottlieb, E. (2009) Cardiolipin acts as a mitochondrial signalling platform to launch apoptosis, Biochim. Biophys. Acta, 1788, 2022-2031, doi: 10.1016/j.bbamem.2009.05.004.

36. Lasagna-Reeves, C. A., Castillo-Carranza, D. L., Sengupta, U., Clos, A. L., Jackson, G. R., et al. (2011) Tau oligomers impair memory and induce synaptic and mitochondrial dysfunction in wild-type mice, Mol. Neurodegener., 6, 39, doi: 10.1186/1750-1326-6-39.

37. Du, H., Guo, L., Yan, S., Sosunov, A. A., McKhann, G. M. and Yan, S. S. (2010) Early deficits in synaptic mitochondria in an Alzheimer’s disease mouse model, Proc. Natl. Acad. Sci. USA, 107, 18670-18675, doi: 10.1073/pnas.1006586107.

38. Esteras, N., Rohrer, J. D., Hardy, J., Wray, S., and Abramov, A. Y. (2017) Mitochondrial hyperpolarization in iPSC-derived neurons from patients of FTDP-17 with 10+16 MAPT mutation leads to oxidative stress and neurodegeneration, Redox Biol., 12, 410-422, doi: 10.1016/j.redox.2017.03.008.

39. Eckert, A., Schulz, K.L., Rhein, V., and Gotz, J. (2010) Convergence of amyloid-beta and tau pathologies on mitochondria in vivo, Mol. Neurobiol., 41, 107-114, doi: 10.1007/s12035-010-8109-5.

40. Tracy, T. E., Madero-Pérez, J., Swaney, D. L., Chang, T. S., Moritz, M., et al. (2022) Tau interactome maps synaptic and mitochondrial processes associated with neurodegeneration, Cell, 185, 712-728, doi: 10.1016/j.cell.2021.12.041.

41. Sanz-Blasco, S., Valero, R. A., Rodriguez-Crespo, I., Villalobos, C., and Nunez, L. (2008) Mitochondrial Ca2+ overload underlies Abeta oligomers neurotoxicity providing an unexpected mechanism of neuroprotection by NSAIDs, PLoS One, 3, e2718, doi: 10.1371/journal.pone.0002718.

42. Pallo, S. P., and Johnson, G. V. W. (2015) Tau facilitates Aβ-induced loss of mitochondrial membrane potential independent of cytosolic calcium fluxes in mouse cortical neurons, Neurosci. Lett., 597, 32-37, doi: 10.1016/j.neulet.2015.04.021.

43. Palikaras, K., Achanta, K., Choi, S., Akbari, M., and Bohr, V. A. (2021) Alteration of mitochondrial homeostasis is an early event in a C. elegans model of human tauopathy, Aging (Albany NY), 13, 23876-23894, doi: 10.18632/aging.203683.

44. Zheng, J., Akbari, M., Schirmer, C., Reynaert, M. L., Loyens, A., et al. (2020) Hippocampal tau oligomerization early in tau pathology coincides with a transient alteration of mitochondrial homeostasis and DNA repair in a mouse model of tauopathy, Acta Neuropathol. Commun., 8, 25, doi: 10.1186/s40478-020-00896-8.

45. Jara, C., Aránguiz, A., Cerpa, W., Tapia-Rojas, C., and Quintanilla, R. A. (2018) Genetic ablation of tau improves mitochondrial function and cognitive abilities in the hippocampus, Redox Biol., 18, 279-294, doi: 10.1016/j.redox.2018.07.010.

46. Jara, C., Cerpa, W., Tapia-Rojas, C., and Quintanilla, R. A. (2021) Tau deletion prevents cognitive impairment and mitochondrial dysfunction age associated by a mechanism dependent on cyclophilin-D, Front. Neurosci., 14, 586710, doi: 10.3389/fnins.2020.586710.

47. Jagasia, R., Grote, P., Westermann, B., and Conradt, B. (2005) DRP-1-mediated mitochondrial fragmentation during EGL-1-induced cell death in C. elegans, Nature, 433, 754-760, doi: 10.1038/nature03316.

48. Malka, F., Guillery, O., Cifuentes-Diaz, C., Guillou, E., Belenguer, P., et al. (2006) Separate fusion of outer and inner mitochondrial membranes, EMBO Rep., 6, 853-859, doi: 10.1038/sj.embor.7400488.

49. Chen, H., Detmer, S. A., Ewald, A. J., Griffin, E. E., Fraser, S. E., et al. (2003) Mitofusins Mfn1 and Mfn2 coordinately regulate mitochondrial fusion and are essential for embryonic development, J. Cell Biol., 160, 189-200, doi: 10.1083/jcb.200211046.

50. Ishihara, N., Fujita, Y., Oka, T., and Mihara, K. (2006) Regulation of mitochondrial morphology through proteolytic cleavage of OPA1, EMBO J., 25, 2966-2977, doi: 10.1038/sj.emboj.7601184.

51. Otara, H., Wang, C., Cleland, M. M., Setoguchi, K., Yokota, S., et al. (2010) Mff is an essential factor for mitochondrial recruitment of Drp1 during mitochondrial fission in mammalian cells, J. Cell Biol., 191, 1141-1158, doi: 10.1083/jcb.201007152.

52. Chan, D. C. (2006) Mitochondria: dynamic organelles in disease, aging, and development, Cell, 125, 1241-1252, doi: 10.1016/j.cell.2006.06.010.

53. Trease, A. J., George, J. W., Roland, N. J., Lichter, E. Z., Emanuel, K., et al. (2022) Hyperphosphorylated human tau accumulates at the synapse, localizing on synaptic mitochondrial outer membranes and disrupting respiration in a mouse model of tauopathy, Front. Mol. Neurosci., 15, 852368, doi: 10.3389/fnmol.2022.852368.

54. Quintanilla, R. A., Tapia-Monsalves, C., Vergara, E. H., Pérez, M. J., and Aranguiz, A. (2020) Truncated tau induces mitochondrial transport failure through the impairment of TRAK2 protein and bioenergetics decline in neuronal cells, Front. Cell Neurosci., 14, 175, doi: 10.3389/fncel.2020.00175.

55. Jeong, Y. Y., Jia, N., Ganesan, D., and Cai, Q. (2022) Broad activation of the PRKN pathway triggers synaptic failure by disrupting synaptic mitochondrial supply in early tauopathy, Autophagy, 18, 1472-1474, doi: 10.1080/15548627.2022.2039987.

56. Jarero-Basulto, J. J., Luna-Munoz, J., Mena, R., Kristofikova, Z., Ripova, D., et al. (2013) Proteolytic cleavage of polymeric tau protein by caspase-3: implications for Alzheimer’s disease, J. Neuropathol. Exp. Neurol., 72, 1145-1161, doi: 10.1097/NEN.0000000000000013.

57. Kopeikina, K. J., Carlson, G. A., Pitstick, R., Ludvigson, A. E., Peters, A., et al. (2011) Tau accumulation causes mitochondrial distribution deficits in neurons in a mouse model of tauopathy and in human Alzheimer’s disease brain, Am. J. Pathol., 179, 2071-2082, doi: 10.1016/j.ajpath.2011.07.004.

58. Plucinska, G., Paquet, D., Hruscha, A., Godinho, L., Haass, C., et al. (2012) In vivo imaging of disease-related mitochondrial dynamics in a vertebrate model system, J. Neurosci., 32, 16203-16212, doi: 10.1523/JNEUROSCI.1327-12.2012.

59. Shahpasand, K., Uemura, I., Saito, T., Asano, T., Hata, K., et al. (2012) Regulation of mitochondrial transport and inter-microtubule spacing by tau phosphorylation at the sites hyperphosphorylated in Alzheimer’s disease, J. Neurosci., 32, 2430-2441, doi: 10.1523/JNEUROSCI.5927-11.2012.

60. Kandimalla, R., Manczak, M., Pradeepkiran, J. A., Morton, H., and Reddy, P. H. (2022) A partial reduction of Drp1 improves cognitive behavior and enhances mitophagy, autophagy and dendritic spines in a transgenic Tau mouse model of Alzheimer disease, Hum. Mol. Genet., 31, 1788-1805, doi: 10.1093/hmg/ddab360.

61. Abtahi, S. L., Masoudi, R., and Haddadi, M. (2020) The distinctive role of tau and amyloid beta in mitochondrial dysfunction through alteration in Mfn2 and Drp1 mRNA levels: a comparative study in Drosophila melanogaster, Gene, 754, 144854, doi: 10.1016/j.gene.2020.144854.

62. Alavi, M. V. (2021) Tau phosphorylation and OPA1 proteolysis are unrelated events: implications for Alzheimer’s disease, Biochim. Biophys. Acta Mol. Cell. Res., 1868, 119116, doi: 10.1016/j.bbamcr.2021.119116.

63. Kerr, J. S., Adriaanse, B. A., Greig, N. H., Mattson, M. P., Cader, M. Z., et al. (2017) Mitophagy and Alzheimer’s disease: cellular and molecular mechanisms, Trends Neurosci., 40, 151-166, doi: 10.1016/j.tins.2017.01.002.

64. Hu, Y., Li, X. C., Wang, Z. H., Luo, Y., Zhang, X., et al. (2016) Tau accumulation impairs mitophagy via increasing mitochondrial membrane potential and reducing mitochondrial Parkin, Oncotarget, 7, 17356-17368, doi: 10.18632/oncotarget.7861.

65. Cummins, N., Tweedie, A., Zuryn, S., Bertran-Gonzalez, J., and Götz, J. (2019) Disease-associated tau impairs mitophagy by inhibiting Parkin translocation to mitochondria, EMBO J., 38, doi: 10.15252/embj.201899360.

66. Corsetti, V., Florenzano, F., Atlante, A., Bobba, A., Ciotti, M. T., et al. (2015) NH2-truncated human tau induces deregulated mitophagy in neurons by aberrant recruitment of Parkin and UCHL-1: implications in Alzheimer’s disease, Hum. Mol. Genet., 24, 3058-3081, doi: 10.1093/hmg/ddv059.

67. Escobar-Henriques, M., and Langer, T. (2014) Dynamic survey of mitochondria by ubiquitin, EMBO Rep., 15, 231-243, doi: 10.1002/embr.201338225.

68. Hegde, A. N., and DiAntonio, A. (2002) Ubiquitin and the synapse, Nat. Rev. Neurosci., 3, 854-861, doi: 10.1038/nrn961.

69. Zhu, X., Perry, G., Smith, M. A., and Wang, X. (2013) Abnormal mitochondrial dynamics in the pathogenesis of Alzheimer’s disease, J. Alzheimer’s Dis., 33, 253-262, doi: 10.3233/JAD-2012-129005.

70. Amadoro, G., Corsetti, V., Florenzano, F., Atlante, A., Bobba, A., et al. (2014) Morphological and bioenergetic demands underlying the mitophagy in post-mitotic neurons: the pink-parkin pathway, Front. Aging Neurosci., 6, 18, doi: 10.3389/fnagi.2014.00018.

71. Reddy, P. H., Tripathi, R., Troung, Q., Tirumala, K., Reddy, T. P., et al. (2012) Abnormal mitochondrial dynamics and synaptic degeneration as early events in Alzheimer’s disease: implications to mitochondria-targeted antioxidant therapeutics, Biochim. Biophys. Acta, 1822, 639-649, doi: 10.1016/j.bbadis.2011.10.011.

72. Koyano, F., Okatsu, K., Ishigaki, S., Fujioka, Y., Kimura, M., et al. (2013) The principal PINK1 and Parkin cellular events triggered in response to dissipation of mitochondrial membrane potential occur in primary neurons, Genes Cells., 18, 672-681, doi: 10.1111/gtc.12066.

73. Bingol, B., Tea, J. S., Phu, L., Reichelt, M., Bakalarski, C. E., et al. (2014) The mitochondrial deubiquitinase USP30 opposes parkin-mediated mitophagy, Nature, 510, 370-375, doi: 10.1038/nature13418.

74. Osaka, H., Wang, Y.L., Takada, K., Takizawa, S., Setsuie, R., et al. (2003) Ubiquitin carboxy-terminal hydrolase L1 binds to and stabilizes monoubiquitin in neuron, Hum. Mol. Genet., 12, 1945-1958, doi: 10.1093/hmg/ddg211.

75. Liu, Y., Fallon, L., Lashuel, H. A., Liu, Z., and Lansbury, P. T., Jr. (2002) The UCH-L1 gene encodes two opposing enzymatic activities that affect alpha-synuclein degradation and Parkinson’s disease susceptibility, Cell, 111, 209-218, doi: 10.1016/s0092-8674(02)01012-7.

76. Cartier, A. E., Djakovic, S. N., Salehi, A., Wilson, S. M., Masliah, E., et al. (2009) Regulation of synaptic structure by ubiquitin C-terminal hydrolase L1, J. Neurosci., 29, 7857-7868, doi: 10.1523/JNEUROSCI.1817-09.2009.

77. Chen, F., Sugiura, Y., Myers, K. G., Liu, Y., and Lin, W. (2010) Ubiquitin carboxyl-terminal hydrolase L1 is required for maintaining the structure and function of the neuromuscular junction, Proc. Natl. Acad. Sci. USA, 107, 1636-1641, doi: 10.1073/pnas.0911516107.

78. Guglielmotto, M., Monteleone, D., Boido, M., Piras, A., Giliberto, L., et al. (2012) Aβ1-42-mediated down-regulation of Uch-L1 is dependent on NF-κB activation and impaired BACE1 lysosomal degradation, Aging Cell, 11, 834-844, doi: 10.1111/j.1474-9726.2012.00854.x.

79. Poon, W. W., Carlos, A. J., Aguilar, B. L., Berchtold, N. C., Kawano, C. K., et al. (2013) β-Amyloid (Aβ) oligomers impair brain-derived neurotrophic factor retrograde trafficking by down-regulating ubiquitin C-terminal hydrolase, UCH-L1, J. Biol. Chem., 288, 16937-16948, doi: 10.1074/jbc.M113.463711.

80. Zanon, A., Rakovic, A., Blankenburg, H., Doncheva, N. T., Schwienbacher, C., et al. (2013) Profiling of Parkin-binding partners using tandem affinity purification, PLoS One, 8, e78648, doi: 10.1371/journal.pone.0078648.

81. Shevtsova, E. F., Maltsev, A. V., Vinogradova, D. V., Shevtsov, P. N., and Bachurin, S. O. (2021) Mitochondria as a promising target for developing novel agents for treating Alzheimer’s disease, Med. Res. Rev., 41, 803-827, doi: 10.1002/med.21715.

82. Johri, A. (2021) Disentangling mitochondria in Alzheimer’s disease, Int. J. Mol. Sci., 22, 11520, doi: 10.3390/ijms222111520.

83. Mary, A., Eysert, F., Checler, F., and Chami, M. (2022) Mitophagy in Alzheimer’s disease: molecular defects and therapeutic approaches, Mol. Psychiatry, doi: 10.1038/s41380-022-01631-6.

84. Kshirsagar, S., Sawant, N., Morton, H., Reddy, A. P., and Reddy, P. H. (2021) Mitophagy enhancers against phosphorylated Tau-induced mitochondrial and synaptic toxicities in Alzheimer’s disease, Pharmacol. Res., 174, 105973, doi: 10.1016/j.phrs.2021.105973.

85. Feniouk, B. A., and Skulachev, V. P. (2017) Cellular and molecular mechanisms of action of mitochondria-targeted antioxidants, Curr. Aging Sci., 10, 41-48, doi: 10.2174/1874609809666160921113706.

86. Plotnikov, E. Y., Silachev, D. N., Jankauskas, S. S., Rokitskaya, T. I., Chupyrkina, A. A., et al. (2012) Mild uncoupling of respiration and phosphorylation as a mechanism providing nephro- and neuroprotective effects of penetrating cations of the SkQ family, Biochemistry (Moscow), 77, 1029-1037, doi: 10.1134/s0006297912090106.

87. Lukashev, A. N., Skulachev, M. V., Ostapenko, V., Savchenko, A. Y., Pavshintsev, V. V., et al. (2014) Advances in development of rechargeable mitochondrial antioxidants, Prog. Mol. Biol. Transl. Sci., 127, 251-265, doi: 10.1016/b978-0-12-394625-6.00010-6.

88. Isaev, N. K., Stelmashook, E. V., Genrikhs, E. E., Korshunova, G. A., Sumbatyan, N. V., et al. (2016) Neuroprotective properties of mitochondria-targeted antioxidants of the SkQ-type, Rev. Neurosci., 27, 849-855, doi: 10.1515/revneuro-2016-0036.

89. Oddo, S., Caccamo, A., Shepherd, J. D., Murphy, M. P., Golde, T. E., et al. (2003) Triple-transgenic model of Alzheimer’s disease with plaques and tangles: intracellular Aβ and synaptic dysfunction, Neuron, 39, 409-421, doi: 10.1016/s0896-6273(03)00434-3.

90. Young, M. L., and Franklin, J. L. (2019) The mitochondria-targeted antioxidant MitoQ inhibits memory loss, neuropathology, and extends lifespan in aged 3xTg-AD mice, Mol. Cell Neurosci., 101, 103409, doi: 10.1016/j.mcn.2019.103409.

91. Samluk, L., Ostapczuk, P., and Dziembowska, M. (2022) Long-term mitochondrial stress induces early steps of Tau aggregation by increasing reactive oxygen species levels and affecting cellular proteostasis, Mol. Biol. Cell, 33, ar67, doi: 10.1091/mbc.E21-11-0553.

92. Stefanova, N. A., Muraleva, N. A., Maksimova, K. Y., Rudnitskaya, E. A., Kiseleva, E., et al. (2016) An antioxidant specifically targeting mitochondria delays progression of Alzheimer’s disease-like pathology, Aging (Albany NY), 8, 2713-2733, doi: 10.18632/aging.101054.

93. Trushina, E., Trushin, S., and Hasan, F. (2022) Mitochondrial complex I as a therapeutic target for Alzheimer’s disease, Acta Pharm. Sin. B, 12, 483-495, doi: 10.1016/j.apsb.2021.11.003.

94. Stojakovic, A., Chang, S. Y., Nesbitt, J., Pichurin, N. P., Ostroot, M. A., et al. (2021) Partial inhibition of mitochondrial complex I reduces tau pathology and improves energy homeostasis and synaptic function in 3xTg-AD mice, J. Alzheimer’s Dis., 79, 335-353, doi: 10.3233/JAD-201015.

95. Singulani, M. P., De Paula, V. J. R., and Forlenza, O. V. (2021) Mitochondrial dysfunction in Alzheimer’s disease: therapeutic implications of lithium, Neurosci. Lett., 760, 136078, doi: 10.1016/j.neulet.2021.136078.

96. Tayanloo-Beik, A., Kiasalari, Z., and Roghani, M. (2022) Paeonol ameliorates cognitive deficits in streptozotocin murine model of sporadic Alzheimer’s disease via attenuation of oxidative stress, inflammation, and mitochondrial dysfunction, J. Mol. Neurosci., 72, 336-348, doi: 10.1007/s12031-021-01936-1.

97. Guo, W., Zeng, Z., Xing, C., Zhang, J., Bi, W., et al. (2022) Stem cells from human exfoliated deciduous teeth affect mitochondria and reverse cognitive decline in a senescence-accelerated mouse prone 8 model, Cytotherapy, 24, 59-71, doi: 10.1016/j.jcyt.2021.07.018.

98. Salehi, P., Shahmirzadi, Z. Y., Mirrezaei, F. S., Boushehri, F. S., Mayahi, F., et al. (2019) A hypothetic role of minocycline as a neuroprotective agent against methylphenidate-induced neuronal mitochondrial dysfunction and tau protein hyper-phosphorylation: possible role of PI3/Akt/GSK3β signaling pathway, Med. Hypotheses, 128, 6-10, doi: 10.1016/j.mehy.2019.04.017.

99. Colman, R. J., Anderson, R. M., Johnson, S. C., Kastman, E. K., Kosmatka, K. J., et al. (2009) Caloric restriction delays disease onset and mortality in rhesus monkeys, Science, 325, 201-204, doi: 10.1126/science.1173635.

100. Sohal, R. S., and Weindruch, R. (1996) Oxidative stress, caloric restriction, and aging, Science, 273, 59-63, doi: 10.1126/science.273.5271.59.

101. Sanz, A., Caro, P., Ibanez, J., Gomez, J., Gredilla, R., et al. (2005) Dietary restriction at old age lowers mitochondrial oxygen radical production and leak at complex I and oxidative DNA damage in rat brain, J. Bioenerg. Biomembr., 37, 83-90, doi: 10.1007/s10863-005-4131-0.

102. Singh, R., Lakhanpal, D., Kumar, S., Sharma, S., Kataria, H., et al. (2012) Late-onset intermittent fasting dietary restriction as a potential intervention to retard age-associated brain function impairments in male rats, Age (Dordr), 34, 917-933, doi: 10.1007/s11357-011-9289-2.

103. Cerqueira, F. M., Cunha, F. M., Laurindo, F. R., and Kowaltowski, A. J. (2012) Calorie restriction increases cerebral mitochondrial respiratory capacity in a NO-mediated mechanism: impact on neuronal survival, Free Radic. Biol. Med., 52, 1236-1241, doi: 10.1016/j.freeradbiomed.2012.01.011.

104. Lambert, A. J., Wang, B., Yardley, J., Edwards, J., and Merry, B. J. (2004) The effect of aging and caloric restriction on mitochondrial protein density and oxygen consumption, Exp. Gerontol., 39, 289-295, doi: 10.1016/j.exger.2003.12.009.

105. Halagappa, V. K. M., Guo, Z., Pearson, M., Matsuoka, Y., Cutler, R. G., et al. (2007) Intermittent fasting and caloric restriction ameliorate age-related behavioral deficits in the triple-transgenic mouse model of Alzheimer’s disease, Neurobiol. Dis., 26, 212-220, doi: 10.1016/j.nbd.2006.12.019.

106. Kang, K., Xu, P., Wang, M., Chunyu, J., Sun, X., et al. (2020) FGF21 attenuates neurodegeneration through modulating neuroinflammation and oxidant-stress, Biomed. Pharmacother., 129, 110439, doi: 10.1016/j.biopha.2020.110439.

107. Mohamed, T. M., Youssef, M. A. M., Bakry, A. A., and El-Keiy, M. M. (2021) Alzheimer’s disease improved through the activity of mitochondrial chain complexes and their gene expression in rats by boswellic acid, Metab. Brain Dis., 36, 255-264, doi: 10.1007/s11011-020-00639-7.

108. Ji, D., Wu, X., Li, D., Liu, P., Zhang, S., et al. (2020) Protective effects of chondroitin sulphate nano-selenium on a mouse model of Alzheimer’s disease, Int. J. Biol. Macromol., 154, 233-245, doi: 10.1016/j.ijbiomac.2020.03.079.

109. Saretzki, G., and Wan, T. (2021) Telomerase in brain: the new kid on the block and its role in neurodegenerative diseases, Biomedicines, 9, 490, doi: 10.3390/biomedicines9050490.