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Effect of Tau Protein on Mitochondrial Functions

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Abstract

Alzheimer’s disease is the most common age-related progressive neurodegenerative disorder of brain cortex and hippocampus leading to cognitive impairment. Accumulation of extracellular amyloid plaques and intraneuronal neurofibrillary tangles are believed to be the main hallmarks of the disease. Origin of Alzheimer’s disease is not totally clear, multiple initiator factors are likely to exist. Intracellular impacts of Alzheimer’s disease include mitochondrial dysfunction, oxidative stress, ER-stress, disruption of autophagy, severe metabolic challenges leading to massive neuronal apoptosis. Mitochondria are the key players in all these processes. This formed the basis for the so-called mitochondrial cascade hypothesis. This review provides current data on the molecular mechanisms of the development of Alzheimer’s disease associated with mitochondria. Special attention was paid to the interaction between Tau protein and mitochondria, as well as to the promising therapeutic approaches aimed at preventing development of neurodegeneration.

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Abbreviations

AD:

Alzheimer’s disease

Drp1:

dynamin-related protein 1

ETC:

electron transport chain

hTau:

full-length human Tau protein

MitoQ:

mitoquinone mesylate

OPA1:

mitochondrial dynamin like GTPase

PINK1:

PTEN-induced kinase 1

P-Tay:

hyperphosphorylated Tau protein

ROS:

reactive oxygen species

SkQ1:

10-(6′-plastoquinonyl)decyltriphenylphosphonium

TRAK2:

trafficking kinesin-binding protein 2

UCHL-1:

ubiquitin carboxy-terminal hydrolase L1

References

  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, https://doi.org/10.4172/2161-0460.1000394.

    Article  Google Scholar 

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

    Article  PubMed  Google Scholar 

  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, https://doi.org/10.1016/j.bbadis.2013.08.013.

    Article  CAS  PubMed  Google Scholar 

  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, https://doi.org/10.1093/hmg/dds072.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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, https://doi.org/10.1007/s12035-020-01945-y.

    Article  CAS  PubMed  Google Scholar 

  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, https://doi.org/10.1016/j.arr.2020.101208.

    Article  CAS  PubMed  Google Scholar 

  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, https://doi.org/10.1042/BST20180025.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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, https://doi.org/10.3233/JAD-2010-100120.

    Article  CAS  Google Scholar 

  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, https://doi.org/10.1074/jbc.M500356200.

    Article  CAS  PubMed  Google Scholar 

  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, https://doi.org/10.1073/pnas.0905529106.

    Article  PubMed  PubMed Central  Google Scholar 

  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, https://doi.org/10.1186/s13024-018-0295-z.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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, https://doi.org/10.1038/srep24756.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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, https://doi.org/10.1007/s12035-017-0385-x.

    Article  CAS  Google Scholar 

  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, https://doi.org/10.1093/cercor/bhw057.

    Article  PubMed  Google Scholar 

  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, https://doi.org/10.1126/science.1194653.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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, https://doi.org/10.1073/pnas.0903563106.

    Article  PubMed  PubMed Central  Google Scholar 

  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, https://doi.org/10.1016/j.freeradbiomed.2008.03.012.

    Article  CAS  PubMed  Google Scholar 

  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, https://doi.org/10.1016/j.exger.2007.10.018.

    Article  CAS  PubMed  Google Scholar 

  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, https://doi.org/10.1016/j.jprot.2010.12.012.

    Article  CAS  Google Scholar 

  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, https://doi.org/10.1093/hmg/ddw312.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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, 488, https://doi.org/10.3390/cells8050488.

    Article  CAS  PubMed Central  Google Scholar 

  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, https://doi.org/10.1002/jnr.24781.

    Article  CAS  PubMed  Google Scholar 

  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, https://doi.org/10.3390/ijms21228727.

    Article  CAS  Google Scholar 

  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, https://doi.org/10.4103/1673-5374.249218.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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, https://doi.org/10.1016/j.freeradbiomed.2021.07.013.

    Article  CAS  PubMed  Google Scholar 

  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, https://doi.org/10.1515/revneuro-2017-0063.

    Article  CAS  PubMed  Google Scholar 

  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, https://doi.org/10.1016/j.bbamem.2019.183064.

    Article  CAS  PubMed  Google Scholar 

  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, https://doi.org/10.1016/j.bbamcr.2015.03.003.

    Article  CAS  PubMed  Google Scholar 

  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, https://doi.org/10.3233/JAD-170356.

    Article  CAS  Google Scholar 

  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, https://doi.org/10.1016/j.bbamem.2013.06.026.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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, https://doi.org/10.1016/j.bbabio.2013.10.006.

    Article  CAS  PubMed  Google Scholar 

  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, https://doi.org/10.1016/j.meteno.2015.11.002.

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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, https://doi.org/10.1186/1750-1326-6-39.

    Article  PubMed  PubMed Central  Google Scholar 

  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, https://doi.org/10.1073/pnas.1006586107.

    Article  PubMed  PubMed Central  Google Scholar 

  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, https://doi.org/10.1016/j.redox.2017.03.008.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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, https://doi.org/10.1007/s12035-010-8109-5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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, https://doi.org/10.1016/j.cell.2021.12.041.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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, https://doi.org/10.1371/journal.pone.0002718.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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, https://doi.org/10.1016/j.neulet.2015.04.021.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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, https://doi.org/10.18632/aging.203683.

    Article  CAS  Google Scholar 

  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, https://doi.org/10.1186/s40478-020-00896-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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, https://doi.org/10.1016/j.redox.2018.07.010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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, https://doi.org/10.3389/fnins.2020.586710.

    Article  PubMed  PubMed Central  Google Scholar 

  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, https://doi.org/10.1038/nature03316.

    Article  CAS  PubMed  Google Scholar 

  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, https://doi.org/10.1038/sj.embor.7400488.

    Article  CAS  Google Scholar 

  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, https://doi.org/10.1083/jcb.200211046.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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, https://doi.org/10.1038/sj.emboj.7601184.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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, https://doi.org/10.1083/jcb.201007152.

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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, https://doi.org/10.3389/fnmol.2022.852368.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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, https://doi.org/10.3389/fncel.2020.00175.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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, https://doi.org/10.1080/15548627.2022.2039987.

    Article  CAS  PubMed  Google Scholar 

  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, https://doi.org/10.1097/NEN.0000000000000013.

    Article  CAS  PubMed  Google Scholar 

  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, https://doi.org/10.1016/j.ajpath.2011.07.004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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, https://doi.org/10.1523/JNEUROSCI.1327-12.2012.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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, https://doi.org/10.1523/JNEUROSCI.5927-11.2012.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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, https://doi.org/10.1093/hmg/ddab360.

    Article  CAS  PubMed  Google Scholar 

  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, https://doi.org/10.1016/j.gene.2020.144854.

    Article  CAS  PubMed  Google Scholar 

  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, https://doi.org/10.1016/j.bbamcr.2021.119116.

    Article  CAS  PubMed  Google Scholar 

  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, https://doi.org/10.1016/j.tins.2017.01.002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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, https://doi.org/10.18632/oncotarget.7861.

    Article  PubMed  PubMed Central  Google Scholar 

  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, e99360, https://doi.org/10.15252/embj.201899360.

    Article  CAS  PubMed  Google Scholar 

  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, https://doi.org/10.1093/hmg/ddv059.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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, https://doi.org/10.3233/JAD-2012-129005.

    Article  CAS  Google Scholar 

  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, https://doi.org/10.3389/fnagi.2014.00018.

    Article  PubMed  PubMed Central  Google Scholar 

  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, https://doi.org/10.1016/j.bbadis.2011.10.011.

    Article  CAS  PubMed  Google Scholar 

  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, https://doi.org/10.1111/gtc.12066.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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, https://doi.org/10.1038/nature13418.

    Article  CAS  PubMed  Google Scholar 

  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, https://doi.org/10.1093/hmg/ddg211.

    Article  CAS  PubMed  Google Scholar 

  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, https://doi.org/10.1016/s0092-8674(02)01012-7.

    Article  CAS  PubMed  Google Scholar 

  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, https://doi.org/10.1523/JNEUROSCI.1817-09.2009.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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, https://doi.org/10.1073/pnas.0911516107.

    Article  PubMed  PubMed Central  Google Scholar 

  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, https://doi.org/10.1111/j.1474-9726.2012.00854.x.

    Article  CAS  PubMed  Google Scholar 

  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, https://doi.org/10.1074/jbc.M113.463711.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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, https://doi.org/10.1371/journal.pone.0078648.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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, https://doi.org/10.1002/med.21715.

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  Google Scholar 

  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, https://doi.org/10.1016/j.phrs.2021.105973.

    Article  CAS  PubMed  Google Scholar 

  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, https://doi.org/10.2174/1874609809666160921113706.

    Article  CAS  PubMed  Google Scholar 

  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, https://doi.org/10.1134/s0006297912090106.

    Article  CAS  Google Scholar 

  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, https://doi.org/10.1016/b978-0-12-394625-6.00010-6.

    Article  PubMed  Google Scholar 

  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, https://doi.org/10.1515/revneuro-2016-0036.

    Article  CAS  PubMed  Google Scholar 

  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, https://doi.org/10.1016/s0896-6273(03)00434-3.

    Article  CAS  PubMed  Google Scholar 

  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, https://doi.org/10.1016/j.mcn.2019.103409.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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, https://doi.org/10.1091/mbc.E21-11-0553.

    Article  CAS  PubMed  Google Scholar 

  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, https://doi.org/10.18632/aging.101054.

    Article  CAS  Google Scholar 

  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, https://doi.org/10.1016/j.apsb.2021.11.003.

    Article  CAS  PubMed  Google Scholar 

  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, https://doi.org/10.3233/JAD-201015.

    Article  CAS  Google Scholar 

  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, https://doi.org/10.1016/j.neulet.2021.136078.

    Article  CAS  PubMed  Google Scholar 

  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, https://doi.org/10.1007/s12031-021-01936-1.

    Article  CAS  PubMed  Google Scholar 

  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, https://doi.org/10.1016/j.jcyt.2021.07.018.

    Article  CAS  PubMed  Google Scholar 

  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, https://doi.org/10.1016/j.mehy.2019.04.017.

    Article  CAS  PubMed  Google Scholar 

  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, https://doi.org/10.1126/science.1173635.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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, https://doi.org/10.1007/s10863-005-4131-0.

    Article  CAS  PubMed  Google Scholar 

  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, https://doi.org/10.1007/s11357-011-9289-2.

    Article  CAS  Google Scholar 

  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, https://doi.org/10.1016/j.freeradbiomed.2012.01.011.

    Article  CAS  PubMed  Google Scholar 

  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, https://doi.org/10.1016/j.exger.2003.12.009.

    Article  CAS  PubMed  Google Scholar 

  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, https://doi.org/10.1016/j.nbd.2006.12.019.

    Article  CAS  PubMed  Google Scholar 

  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, https://doi.org/10.1016/j.biopha.2020.110439.

    Article  CAS  PubMed  Google Scholar 

  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, https://doi.org/10.1007/s11011-020-00639-7.

    Article  CAS  PubMed  Google Scholar 

  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, https://doi.org/10.1016/j.ijbiomac.2020.03.079.

    Article  CAS  PubMed  Google Scholar 

  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, https://doi.org/10.3390/biomedicines9050490.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Funding

This research was financially supported in part by the Russian Foundation for Basic Research (grant no. 19-34-90165).

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  1. Bach Institute of Biochemistry, Federal Research Center of Biotechnology, Russian Academy of Sciences, 119071, Moscow, Russia

    Khoren K. Epremyan, Tatyana N. Goleva & Renata A. Zvyagilskaya

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K. K. Epremyan, R. A. Zvyagilskaya – concept and management; K. K. Epremyan – writing the text; R. A. Zvyagilskaya, T. N. Goleva – editing the text of the article.

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Correspondence to Khoren K. Epremyan.

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Epremyan, K.K., Goleva, T.N. & Zvyagilskaya, R.A. Effect of Tau Protein on Mitochondrial Functions. Biochemistry Moscow 87, 689–701 (2022). https://doi.org/10.1134/S0006297922080028

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