Mitochondrial Medicine: A Promising Therapeutic Option Against Various
Neurodegenerative Disorders

Mohannad   A.   Almikhlafi; Mohammed   M.   Karami; Ankit      Jana; Thamer   M.   Alqurashi; Mohammed      Majrashi; Badrah   S.   Alghamdi; Ghulam   Md.   Ashraf
Abstract

Abnormal mitochondrial morphology and metabolic dysfunction have been observed in many neurodegenerative disorders (NDDs). Mitochondrial dysfunction can be caused by aberrant mitochondrial DNA, mutant nuclear proteins that interact with mitochondria directly or indirectly, or for unknown reasons. Since mitochondria play a significant role in neurodegeneration, mitochondriatargeted therapies represent a prosperous direction for the development of novel drug compounds that can be used to treat NDDs. This review gives a brief description of how mitochondrial abnormalities lead to various NDDs such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis. We further explore the promising therapeutic effectiveness of mitochondria- directed antioxidants, MitoQ, MitoVitE, MitoPBN, and dimebon. We have also discussed the possibility of mitochondrial gene therapy as a therapeutic option for these NDDs.
Keywords: Alzheimer’s disease, Amyotrophic lateral sclerosis, Gene therapy, Huntington’s disease, Mitochondrial dysfunction, Parkinson’s disease.
Graphical Abstract

[1]
Harris, J.J.; Jolivet, R.; Attwell, D. Synaptic energy use and supply. Neuron,  2012, 75(5), 762-777.
 [http://dx.doi.org/10.1016/j.neuron.2012.08.019] [PMID:  22958818]

[2]
Moreira, P.I.; Santos, M.S.; Oliveira, C.R. Alzheimer’s disease: A lesson from mitochondrial dysfunction. Antioxid. Redox Signal.,  2007, 9(10), 1621-1630.
 [http://dx.doi.org/10.1089/ars.2007.1703] [PMID:  17678440]

[3]
Duchen, M.R. Mitochondria and calcium: From cell signalling to cell death. J. Physiol.,  2000, 529(Pt 1), 57-68.
 [http://dx.doi.org/10.1111/j.1469-7793.2000.00057.x]

[4]
Susin, S.A.; Lorenzo, H.K.; Zamzami, N.; Marzo, I.; Snow, B.E.; Brothers, G.M.; Mangion, J.; Jacotot, E.; Costantini, P.; Loeffler, M.; Larochette, N.; Goodlett, D.R.; Aebersold, R.; Siderovski, D.P.; Penninger, J.M.; Kroemer, G. Molecular characterization of mitochondrial apoptosis-inducing factor. Nature,  1999, 397(6718), 441-446.
 [http://dx.doi.org/10.1038/17135] [PMID:  9989411]

[5]
Budd, S.L.; Nicholls, D.G. Mitochondria in the life and death of neurons. Essays Biochem.,  1998, 33, 43-52.
 [http://dx.doi.org/10.1042/bse0330043] [PMID:  10488440]

[6]
Finkel, T. Radical medicine: Treating ageing to cure disease. Nat. Rev. Mol. Cell Biol.,  2005, 6(12), 971-976.
 [http://dx.doi.org/10.1038/nrm1763] [PMID:  16227974]

[7]
Fiskum, G. Mitochondrial participation in ischemic and traumatic neural cell death. J. Neurotrauma,  2000, 17(10), 843-855.
 [http://dx.doi.org/10.1089/neu.2000.17.843] [PMID:  11063052]

[8]
Moreira, P.I.; Duarte, A.I.; Santos, M.S.; Rego, A.C.; Oliveira, C.R. An integrative view of the role of oxidative stress, mitochondria and insulin in Alzheimer’s disease. J. Alzheimers Dis.,  2009, 16(4), 741-761.
 [http://dx.doi.org/10.3233/JAD-2009-0972] [PMID:  19387110]

[9]
Sullivan, P.G.; Keller, J.N.; Mattson, M.P.; Scheff, S.W. Traumatic brain injury alters synaptic homeostasis: Implications for impaired mitochondrial and transport function. J. Neurotrauma,  1998, 15(10), 789-798.
 [http://dx.doi.org/10.1089/neu.1998.15.789] [PMID:  9814635]

[10]
Zorov, D.B.; Juhaszova, M.; Sollott, S.J. Mitochondrial reactive oxygen species (ROS) and ROS-induced ROS release. Physiol. Rev.,  2014, 94(3), 909-950.
 [http://dx.doi.org/10.1152/physrev.00026.2013] [PMID:  24987008]

[11]
Valko, M.; Leibfritz, D.; Moncol, J.; Cronin, M.T.D.; Mazur, M.; Telser, J. Free radicals and antioxidants in normal physiological functions and human disease. Int. J. Biochem. Cell Biol.,  2007, 39(1), 44-84.
 [http://dx.doi.org/10.1016/j.biocel.2006.07.001] [PMID:  16978905]

[12]
Moreira, P.I.; Nunomura, A.; Nakamura, M.; Takeda, A.; Shenk, J.C.; Aliev, G.; Smith, M.A.; Perry, G. Nucleic acid oxidation in Alzheimer disease. Free Radic. Biol. Med.,  2008, 44(8), 1493-1505.
 [http://dx.doi.org/10.1016/j.freeradbiomed.2008.01.002] [PMID:  18258207]

[13]
Islam, Md. T. Oxidative stress and mitochondrial dysfunction-linked neurodegenerative disorders. Neurol. Res.,  2017, 39(1), 73-82.
 [http://dx.doi.org/10.1080/01616412.2016.1251711] [PMID:  27809706]

[14]
Singh, A.; Kukreti, R.; Saso, L.; Kukreti, S. Oxidative stress: A key modulator in neurodegenerative diseases. Molecules,  2019, 24(8), 1583.
 [http://dx.doi.org/10.3390/molecules24081583] [PMID:  31013638]

[15]
Reddy, P.H. Amyloid precursor protein-mediated free radicals and oxidative damage: Implications for the development and progression of Alzheimer’s disease. J. Neurochem.,  2006, 96(1), 1-13.
 [http://dx.doi.org/10.1111/j.1471-4159.2005.03530.x] [PMID:  16305625]

[16]
Schapira, A.H.V. Mitochondrial disease. Lancet,  2006, 368(9529), 70-82.
 [http://dx.doi.org/10.1016/S0140-6736(06)68970-8] [PMID:  16815381]

[17]
Swerdlow, R.H.; Burns, J.M.; Khan, S.M. The Alzheimer’s disease mitochondrial cascade hypothesis. J. Alzheimers Dis.,  2010, 20(Suppl. 2), S265-S279.
 [http://dx.doi.org/10.3233/JAD-2010-100339]

[18]
Wallace, D.C. A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: A dawn for evolutionary medicine. Annu. Rev. Genet.,  2005, 39(1), 359-407.
 [http://dx.doi.org/10.1146/annurev.genet.39.110304.095751] [PMID:  16285865]

[19]
Ventura-Clapier, R.; Garnier, A.; Veksler, V. Transcriptional control of mitochondrial biogenesis: The central role of PGC-1. Cardiovasc. Res.,  2008, 79(2), 208-217.
 [http://dx.doi.org/10.1093/cvr/cvn098] [PMID:  18430751]

[20]
Zhu, J.; Wang, K.Z.Q.; Chu, C.T. After the banquet. Autophagy,  2013, 9(11), 1663-1676.
 [http://dx.doi.org/10.4161/auto.24135] [PMID:  23787782]

[21]
Uittenbogaard, M.; Chiaramello, A. Mitochondrial biogenesis: A therapeutic target for neurodevelopmental disorders and neurodegenerative diseases. Curr. Pharm. Des.,  2014, 20(35), 5574-5593.
 [http://dx.doi.org/10.2174/1381612820666140305224906] [PMID:  24606804]

[22]
Twig, G.; Elorza, A.; Molina, A.J.A.; Mohamed, H.; Wikstrom, J.D.; Walzer, G.; Stiles, L.; Haigh, S.E.; Katz, S.; Las, G.; Alroy, J.; Wu, M.; Py, B.F.; Yuan, J.; Deeney, J.T.; Corkey, B.E.; Shirihai, O.S. Fission and selective fusion govern mitochondrial segregation and elimination by autophagy. EMBO J.,  2008, 27(2), 433-446.
 [http://dx.doi.org/10.1038/sj.emboj.7601963] [PMID:  18200046]

[23]
Siesjö, B.K. Brain metabolism and anaesthesia. Acta Anaesthesiol. Scand. Suppl.,  1978, 70, 56-59.
 [PMID:  283672]

[24]
Rolfe, D.F.; Brown, G.C. Cellular energy utilization and molecular origin of standard metabolic rate in mammals. Physiol. Rev.,  1997, 77(3), 731-758.
 [http://dx.doi.org/10.1152/physrev.1997.77.3.731] [PMID:  9234964]

[25]
Guo, R.; Zong, S.; Wu, M.; Gu, J.; Yang, M. Architecture of human mitochondrial respiratory megacomplex I2III2IV2. Cell,  2017, 170(6), 1247-1257.e12.
 [http://dx.doi.org/10.1016/j.cell.2017.07.050] [PMID:  28844695]

[26]
Iwata, S.; Lee, J.W.; Okada, K.; Lee, J.K.; Iwata, M.; Rasmussen, B.; Link, T.A.; Ramaswamy, S.; Jap, B.K. Complete structure of the 11-subunit bovine mitochondrial cytochrome bc1 complex. Science,  1998, 281(5373), 64-71.
 [http://dx.doi.org/10.1126/science.281.5373.64] [PMID:  9651245]

[27]
Westermann, B. Mitochondrial fusion and fission in cell life and death. Nat. Rev. Mol. Cell Biol.,  2010, 11(12), 872-884.
 [http://dx.doi.org/10.1038/nrm3013] [PMID:  21102612]

[28]
Lee, H.; Smith, S.B.; Yoon, Y. The short variant of the mitochondrial dynamin OPA1 maintains mitochondrial energetics and cristae structure. J. Biol. Chem.,  2017, 292(17), 7115-7130.
 [http://dx.doi.org/10.1074/jbc.M116.762567] [PMID:  28298442]

[29]
Ishihara, N.; Eura, Y.; Mihara, K. Mitofusin 1 and 2 play distinct roles in mitochondrial fusion reactions via GTPase activity. J. Cell Sci.,  2004, 117(26), 6535-6546.
 [http://dx.doi.org/10.1242/jcs.01565] [PMID:  15572413]

[30]
Koshiba, T.; Detmer, S.A.; Kaiser, J.T.; Chen, H.; McCaffery, J.M.; Chan, D.C. Structural basis of mitochondrial tethering by mitofusin complexes. Science,  2004, 305(5685), 858-862.
 [http://dx.doi.org/10.1126/science.1099793] [PMID:  15297672]

[31]
Chan, D.C. Mitochondrial dynamics and its involvement in disease. Annu. Rev. Pathol.,  2020, 15(1), 235-259.
 [http://dx.doi.org/10.1146/annurev-pathmechdis-012419-032711] [PMID:  31585519]

[32]
Cipolat, S.; de Brito, O.M.; Dal Zilio, B.; Scorrano, L. OPA1 requires mitofusin 1 to promote mitochondrial fusion. Proc. Natl. Acad. Sci. USA,  2004, 101(45), 15927-15932.
 [http://dx.doi.org/10.1073/pnas.0407043101] [PMID:  15509649]

[33]
Smirnova, E.; Griparic, L.; Shurland, D.L.; van der Bliek, A.M. Dynamin-related protein Drp1 is required for mitochondrial division in mammalian cells. Mol. Biol. Cell,  2001, 12(8), 2245-2256.
 [http://dx.doi.org/10.1091/mbc.12.8.2245] [PMID:  11514614]

[34]
Waterham, H.R.; Koster, J.; van Roermund, C.W.T.; Mooyer, P.A.W.; Wanders, R.J.A.; Leonard, J.V. A lethal defect of mitochondrial and peroxisomal fission. N. Engl. J. Med.,  2007, 356(17), 1736-1741.
 [http://dx.doi.org/10.1056/NEJMoa064436] [PMID:  17460227]

[35]
Lee, Y.; Jeong, S.Y.; Karbowski, M.; Smith, C.L.; Youle, R.J. Roles of the mammalian mitochondrial fission and fusion mediators Fis1, Drp1, and Opa1 in apoptosis. Mol. Biol. Cell,  2004, 15(11), 5001-5011.
 [http://dx.doi.org/10.1091/mbc.e04-04-0294] [PMID:  15356267]

[36]
Palmer, C.S.; Osellame, L.D.; Laine, D.; Koutsopoulos, O.S.; Frazier, A.E.; Ryan, M.T. MiD49 and MiD51, new components of the mitochondrial fission machinery. EMBO Rep.,  2011, 12(6), 565-573.
 [http://dx.doi.org/10.1038/embor.2011.54] [PMID:  21508961]

[37]
Jakobs, S.; Martini, N.; Schauss, A.C.; Egner, A.; Westermann, B.; Hell, S.W. Spatial and temporal dynamics of budding yeast mitochondria lacking the division component Fis1p. J. Cell Sci.,  2003, 116(10), 2005-2014.
 [http://dx.doi.org/10.1242/jcs.00423] [PMID:  12679388]

[38]
Sweeney, P.; Park, H.; Baumann, M.; Dunlop, J.; Frydman, J.; Kopito, R.; McCampbell, A.; Leblanc, G.; Venkateswaran, A.; Nurmi, A.; Hodgson, R. Protein misfolding in neurodegenerative diseases: Implications and strategies. Transl. Neurodegener.,  2017, 6(1), 6.
 [http://dx.doi.org/10.1186/s40035-017-0077-5] [PMID:  28293421]

[39]
Larsen, S.B.; Hanss, Z.; Krüger, R. The genetic architecture of mitochondrial dysfunction in Parkinson’s disease. Cell Tissue Res.,  2018, 373(1), 21-37.
 [http://dx.doi.org/10.1007/s00441-017-2768-8] [PMID:  29372317]

[40]
Kaufman, D.M.; Wu, X.; Scott, B.A.; Itani, O.A.; Van Gilst, M.R.; Bruce, J.E.; Michael Crowder, C. Ageing and hypoxia cause protein aggregation in mitochondria. Cell Death Differ.,  2017, 24(10), 1730-1738.
 [http://dx.doi.org/10.1038/cdd.2017.101] [PMID:  28644434]

[41]
Gitschlag, B.L.; Kirby, C.S.; Samuels, D.C.; Gangula, R.D.; Mallal, S.A.; Patel, M.R. Homeostatic responses regulate selfish mitochondrial genome dynamics in C. elegans. Cell Metab.,  2016, 24(1), 91-103.
 [http://dx.doi.org/10.1016/j.cmet.2016.06.008] [PMID:  27411011]

[42]
Lin, Y.F.; Schulz, A.M.; Pellegrino, M.W.; Lu, Y.; Shaham, S.; Haynes, C.M. Maintenance and propagation of a deleterious mitochondrial genome by the mitochondrial unfolded protein response. Nature,  2016, 533(7603), 416-419.
 [http://dx.doi.org/10.1038/nature17989] [PMID:  27135930]

[43]
Calabrese, V.; Mancuso, C.; Calvani, M.; Rizzarelli, E.; Butterfield, D.A.; Giuffrida Stella, A.M. Nitric oxide in the central nervous system: Neuroprotection versus neurotoxicity. Nat. Rev. Neurosci.,  2007, 8(10), 766-775.
 [http://dx.doi.org/10.1038/nrn2214] [PMID:  17882254]

[44]
Calabrese, V.; Cornelius, C.; Mancuso, C.; Pennisi, G.; Calafato, S.; Bellia, F.; Bates, T.E.; Giuffrida Stella, A.M.; Schapira, T.; Dinkova Kostova, A.T.; Rizzarelli, E. Cellular stress response: A novel target for chemoprevention and nutritional neuroprotection in aging, neurodegenerative disorders and longevity. Neurochem. Res.,  2008, 33(12), 2444-2471.
 [http://dx.doi.org/10.1007/s11064-008-9775-9] [PMID:  18629638]

[45]
Cornelius, C.; Perrotta, R.; Graziano, A.; Calabrese, E.; Calabrese, V. Stress responses, vitagenes and hormesis as critical determinants in aging and longevity: Mitochondria as a “chi”. Immun. Ageing,  2013, 10, 15.

[46]
Calabrese, V.; Cornelius, C.; Dinkova-Kostova, A.T.; Calabrese, E.J.; Mattson, M.P. Cellular stress responses, the hormesis paradigm, and vitagenes: Novel targets for therapeutic intervention in neurodegenerative disorders. Antioxid. Redox Signal.,  2010, 13(11), 1763-1811.
 [http://dx.doi.org/10.1089/ars.2009.3074] [PMID:  20446769]

[47]
Trovato Salinaro, A.; Pennisi, M.; Di Paola, R.; Scuto, M.; Crupi, R.; Cambria, M.T.; Ontario, M.L.; Tomasello, M.; Uva, M.; Maiolino, L.; Calabrese, E.J.; Cuzzocrea, S.; Calabrese, V. Neuroinflammation and neurohormesis in the pathogenesis of Alzheimer’s disease and Alzheimer-linked pathologies: Modulation by nutritional mushrooms. Immun. Ageing,  2018, 15(1), 8.
 [http://dx.doi.org/10.1186/s12979-017-0108-1] [PMID:  29456585]

[48]
Iuso, A.; Scacco, S.; Piccoli, C.; Bellomo, F.; Petruzzella, V.; Trentadue, R.; Minuto, M.; Ripoli, M.; Capitanio, N.; Zeviani, M.; Papa, S. Dysfunctions of cellular oxidative metabolism in patients with mutations in the NDUFS1 and NDUFS4 genes of complex I. J. Biol. Chem.,  2006, 281(15), 10374-10380.
 [http://dx.doi.org/10.1074/jbc.M513387200] [PMID:  16478720]

[49]
Distelmaier, F.; Visch, H.J.; Smeitink, J.A.M.; Mayatepek, E.; Koopman, W.J.H.; Willems, P.H.G.M. The antioxidant Trolox restores mitochondrial membrane potential and Ca2+-stimulated ATP production in human complex I deficiency. J. Mol. Med. (Berl.),  2009, 87(5), 515-522.
 [http://dx.doi.org/10.1007/s00109-009-0452-5] [PMID:  19255735]

[50]
Morán, M.; Rivera, H.; Sánchez-Aragó, M.; Blázquez, A.; Merinero, B.; Ugalde, C.; Arenas, J.; Cuezva, J.M.; Martín, M.A. Mitochondrial bioenergetics and dynamics interplay in complex I-deficient fibroblasts. Biochim. Biophys. Acta Mol. Basis Dis.,  2010, 1802(5), 443-453.
 [http://dx.doi.org/10.1016/j.bbadis.2010.02.001] [PMID:  20153825]

[51]
Luft, R. The development of mitochondrial medicine. Proc. Natl. Acad. Sci. USA,  1994, 91(19), 8731-8738.

[52]
Smeitink, J.; Ruitenbeek, W.; Lith, T.; Sengers, R.; Trijbels, F.; Wevers, R.; Sperl, W.; de Graaf, R. Maturation of mitochondrial and other isoenzymes of creatine kinase in skeletal muscle of preterm born infants. Ann. Clin. Biochem.,  1992, 29(3), 302-306.
 [http://dx.doi.org/10.1177/000456329202900309] [PMID:  1319128]

[53]
Lin, M.T.; Beal, M.F. Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature,  2006, 443(7113), 787-795.
 [http://dx.doi.org/10.1038/nature05292] [PMID:  17051205]

[54]
Zeviani, M.; Carelli, V. Mitochondrial disorders. Curr. Opin. Neurol.,  2007, 20(5), 564-571.
 [http://dx.doi.org/10.1097/WCO.0b013e3282ef58cd] [PMID:  17885446]

[55]
Aksenov, M.Y.; Tucker, H.M.; Nair, P.; Aksenova, M.V.; Butterfield, D.A.; Estus, S.; Markesbery, W.R. The expression of several mitochondrial and nuclear genes encoding the subunits of electron transport chain enzyme complexes, cytochrome c oxidase, and NADH dehydrogenase, in different brain regions in Alzheimer’s disease. Neurochem. Res.,  1999, 24(6), 767-774.
 [http://dx.doi.org/10.1023/A:1020783614031] [PMID:  10447460]

[56]
Fukuyama, R.; Hatanpää, K.; Rapoport, S.I.; Chandrasekaran, K. Gene expression of ND4, a subunit of complex I of oxidative phosphorylation in mitochondria, is decreased in temporal cortex of brains of Alzheimer’s disease patients. Brain Res.,  1996, 713(1-2), 290-293.
 [http://dx.doi.org/10.1016/0006-8993(95)01517-5] [PMID:  8725003]

[57]
Chandrasekaran, K.; Hatanpää, K.; Brady, D.R.; Rapoport, S.I. Evidence for physiological down-regulation of brain oxidative phosphorylation in Alzheimer’s disease. Exp. Neurol.,  1996, 142(1), 80-88.
 [http://dx.doi.org/10.1006/exnr.1996.0180] [PMID:  8912900]

[58]
Parker, W.D., Jr; Ba, J.P.; Filley, C.M.; Kleinschmidt-DeMasters, B.K. Electron transport chain defects in Alzheimer’s disease brain. Neurology,  1994, 44(6), 1090-1096.
 [http://dx.doi.org/10.1212/WNL.44.6.1090] [PMID:  8208407]

[59]
Manczak, M.; Park, B.S.; Jung, Y.; Reddy, P.H. Differential expression of oxidative phosphorylation genes in patients with Alzheimer’s disease: Implications for early mitochondrial dysfunction and oxidative damage. Neuromol. Med.,  2004, 5(2), 147-162.
 [http://dx.doi.org/10.1385/NMM:5:2:147] [PMID:  15075441]

[60]
Vila, M.; Przedborski, S. Targeting programmed cell death in neurodegenerative diseases. Nat. Rev. Neurosci.,  2003, 4(5), 365-375.
 [http://dx.doi.org/10.1038/nrn1100] [PMID:  12728264]

[61]
Dauer, W.; Przedborski, S. Parkinson’s disease. Neuron,  2003, 39(6), 889-909.
 [http://dx.doi.org/10.1016/S0896-6273(03)00568-3] [PMID:  12971891]

[62]
Betarbet, R.; Sherer, T.B.; MacKenzie, G.; Garcia-Osuna, M.; Panov, A.V.; Greenamyre, J.T. Chronic systemic pesticide exposure reproduces features of Parkinson’s disease. Nat. Neurosci.,  2000, 3(12), 1301-1306.
 [http://dx.doi.org/10.1038/81834] [PMID:  11100151]

[63]
Qi, X.; Lewin, A.S.; Hauswirth, W.W.; Guy, J. Suppression of complex I gene expression induces optic neuropathy. Ann. Neurol.,  2003, 53(2), 198-205.
 [http://dx.doi.org/10.1002/ana.10426] [PMID:  12557286]

[64]
Fato, R.; Bergamini, C.; Leoni, S.; Strocchi, P.; Lenaz, G. Generation of reactive oxygen species by mitochondrial complex I: Implications in neurodegeneration. Neurochem. Res.,  2008, 33(12), 2487-2501.
 [http://dx.doi.org/10.1007/s11064-008-9747-0] [PMID:  18535905]

[65]
Miyoshi, H. Structure–activity relationships of some complex I inhibitors. Biochim. Biophys. Acta Bioenerg.,  1998, 1364(2), 236-244.
 [http://dx.doi.org/10.1016/S0005-2728(98)00030-9] [PMID:  9593914]

[66]
Degli Esposti, M. Inhibitors of NADH–ubiquinone reductase: An overview. Biochim. Biophys. Acta Bioenerg.,  1998, 1364(2), 222-235.
 [http://dx.doi.org/10.1016/S0005-2728(98)00029-2]

[67]
Vila, M.; Jackson-Lewis, V.; Vukosavic, S.; Djaldetti, R.; Liberatore, G.; Offen, D.; Korsmeyer, S.J.; Przedborski, S. Bax ablation prevents dopaminergic neurodegeneration in the 1-methyl- 4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson’s disease. Proc. Natl. Acad. Sci. USA,  2001, 98(5), 2837-2842.
 [http://dx.doi.org/10.1073/pnas.051633998] [PMID:  11226327]

[68]
Chin, M.H.; Qian, W.J.; Wang, H.; Petyuk, V.A.; Bloom, J.S.; Sforza, D.M.; Laćan, G.; Liu, D.; Khan, A.H.; Cantor, R.M.; Bigelow, D.J.; Melega, W.P.; Camp, D.G., II; Smith, R.D.; Smith, D.J. Mitochondrial dysfunction, oxidative stress, and apoptosis revealed by proteomic and transcriptomic analyses of the striata in two mouse models of Parkinson’s disease. J. Proteome Res.,  2008, 7(2), 666-677.
 [http://dx.doi.org/10.1021/pr070546l] [PMID:  18173235]

[69]
Starkov, A.A. The role of mitochondria in reactive oxygen species metabolism and signaling. Ann. N. Y. Acad. Sci.,  2008, 1147(1), 37-52.
 [http://dx.doi.org/10.1196/annals.1427.015] [PMID:  19076429]

[70]
Murphy, M.P. How mitochondria produce reactive oxygen species. Biochem. J.,  2009, 417(1), 1-13.
 [http://dx.doi.org/10.1042/BJ20081386] [PMID:  19061483]

[71]
Turrens, J.F. Mitochondrial formation of reactive oxygen species. J. Physiol.,  2003, 552(2), 335-344.
 [http://dx.doi.org/10.1113/jphysiol.2003.049478] [PMID:  14561818]

[72]
Verkaart, S. Superoxide production is inversely related to complex I activity in inherited complex I deficiency. Biochim. Biophys. Acta Mol. Basis Dis.,  1772, 2007, 373-381.
 [PMID:  33303240]

[73]
Verkaart, S.; Koopman, W.J.H.; Cheek, J.; van Emst-de Vries, S.E.; van den Heuvel, L.W.P.J.; Smeitink, J.A.M.; Willems, P.H.G.M. Mitochondrial and cytosolic thiol redox state are not detectably altered in isolated human NADH:ubiquinone oxidoreductase deficiency. Biochim. Biophys. Acta Mol. Basis Dis.,  2007, 1772(9), 1041-1051.
 [http://dx.doi.org/10.1016/j.bbadis.2007.05.004] [PMID:  17600689]

[74]
Hinson, J.T.; Fantin, V.R.; Schönberger, J.; Breivik, N.; Siem, G.; McDonough, B.; Sharma, P.; Keogh, I.; Godinho, R.; Santos, F.; Esparza, A.; Nicolau, Y.; Selvaag, E.; Cohen, B.H.; Hoppel, C.L.; Tranebjærg, L.; Eavey, R.D.; Seidman, J.G.; Seidman, C.E. Missense mutations in the BCS1L gene as a cause of the Björnstad syndrome. N. Engl. J. Med.,  2007, 356(8), 809-819.
 [http://dx.doi.org/10.1056/NEJMoa055262] [PMID:  17314340]

[75]
Diaz, F.; Enríquez, J.A.; Moraes, C.T. Cells lacking Rieske iron-sulfur protein have a reactive oxygen species-associated decrease in respiratory complexes I and IV. Mol. Cell. Biol.,  2012, 32(2), 415-429.
 [http://dx.doi.org/10.1128/MCB.06051-11] [PMID:  22106410]

[76]
Krause, K.H.; Bedard, K. NOX enzymes in immuno-inflammatory pathologies. Semin. Immunopathol.,  2008, 30(3), 193-194.
 [http://dx.doi.org/10.1007/s00281-008-0127-2] [PMID:  18560833]

[77]
Andreyev, A.Y.; Kushnareva, Y.E.; Starkov, A.A. Mitochondrial metabolism of reactive oxygen species. Biochemistry (Mosc.),  2005, 70(2), 200-214.
 [http://dx.doi.org/10.1007/s10541-005-0102-7] [PMID:  15807660]

[78]
Dröge, W. Free radicals in the physiological control of cell function. Physiol. Rev.,  2002, 82(1), 47-95.
 [http://dx.doi.org/10.1152/physrev.00018.2001] [PMID:  11773609]

[79]
Qin, B.; Cartier, L.; Dubois-Dauphin, M.; Li, B.; Serrander, L.; Krause, K.H. A key role for the microglial NADPH oxidase in APP-dependent killing of neurons. Neurobiol. Aging,  2006, 27(11), 1577-1587.
 [http://dx.doi.org/10.1016/j.neurobiolaging.2005.09.036] [PMID:  16260066]

[80]
Zhang, Y.; Dawson, V.L.; Dawson, T.M. Oxidative stress and genetics in the pathogenesis of Parkinson’s disease. Neurobiol. Dis.,  2000, 7(4), 240-250.
 [http://dx.doi.org/10.1006/nbdi.2000.0319] [PMID:  10964596]

[81]
Andreyev, A.Y.; Kushnareva, Y.E.; Murphy, A.N.; Starkov, A.A.; Mitochondrial, R.O.S. Metabolism: 10 years later. Biochem. Biokhimiia.,  2015, 80(5), 517-531.
 [http://dx.doi.org/10.1134/S0006297915050028]

[82]
Liu, Y.; Fiskum, G.; Schubert, D. Generation of reactive oxygen species by the mitochondrial electron transport chain. J. Neurochem.,  2002, 80(5), 780-787.
 [http://dx.doi.org/10.1046/j.0022-3042.2002.00744.x] [PMID:  11948241]

[83]
Mailer, K. Superoxide radical as electron donor for oxidative phosphorylation of ADP. Biochem. Biophys. Res. Commun.,  1990, 170(1), 59-64.
 [http://dx.doi.org/10.1016/0006-291X(90)91240-S] [PMID:  2164811]

[84]
Smeitink, J.; van den Heuvel, L.; DiMauro, S. The genetics and pathology of oxidative phosphorylation. Nat. Rev. Genet.,  2001, 2(5), 342-352.
 [http://dx.doi.org/10.1038/35072063] [PMID:  11331900]

[85]
Maker, H.S.; Weiss, C.; Silides, D.J.; Cohen, G. Coupling of dopamine oxidation (monoamine oxidase activity) to glutathione oxidation via the generation of hydrogen peroxide in rat brain homogenates. J. Neurochem.,  1981, 36(2), 589-593.
 [http://dx.doi.org/10.1111/j.1471-4159.1981.tb01631.x] [PMID:  7463078]

[86]
Zoccarato, F.; Toscano, P.; Alexandre, A. Dopamine-derived dopaminochrome promotes H2O2 release at mitochondrial complex I: Stimulation by rotenone, control by Ca2+, and relevance to Parkinson disease. J. Biol. Chem.,  2005, 280(16), 15587-15594.
 [http://dx.doi.org/10.1074/jbc.M500657200] [PMID:  15710606]

[87]
Guo, J.; Lemire, B.D. The ubiquinone-binding site of the Saccharomyces cerevisiae succinate-ubiquinone oxidoreductase is a source of superoxide. J. Biol. Chem.,  2003, 278(48), 47629-47635.
 [http://dx.doi.org/10.1074/jbc.M306312200] [PMID:  13129931]

[88]
Brouillet, E.; Condé, F.; Beal, M.F.; Hantraye, P. Replicating Huntington’s disease phenotype in experimental animals. Prog. Neurobiol.,  1999, 59(5), 427-468.
 [http://dx.doi.org/10.1016/S0301-0082(99)00005-2] [PMID:  10515664]

[89]
Liot, G.; Bossy, B.; Lubitz, S.; Kushnareva, Y.; Sejbuk, N.; Bossy-Wetzel, E. Complex II inhibition by 3-NP causes mitochondrial fragmentation and neuronal cell death via an NMDA- and ROS-dependent pathway. Cell Death Differ.,  2009, 16(6), 899-909.
 [http://dx.doi.org/10.1038/cdd.2009.22] [PMID:  19300456]

[90]
Jenner, P. Oxidative stress and Parkinson’s disease. Handb. Clin. Neurol.,  2007, 83, 507-520.
 [http://dx.doi.org/10.1016/S0072-9752(07)83024-7] [PMID:  18808931]

[91]
Chen, V.T.; Huang, C.L.; Lee, Y.C.; Liao, W.C.; Huang, N.K. The roles of the thioredoxin system and peroxiredoxins in 1-methyl-4-phenyl-pyridinium ion-induced cytotoxicity in rat pheochromocytoma cells. Toxicol. In Vitro,  2010, 24(6), 1577-1583.

[92]
Reddy, P.H.; Beal, M.F. Are mitochondria critical in the pathogenesis of Alzheimer’s disease? Brain Res. Brain Res. Rev.,  2005, 49(3), 618-632.
 [http://dx.doi.org/10.1016/j.brainresrev.2005.03.004] [PMID:  16269322]

[93]
Allanbutterfield, D.; Castegna, A.; Lauderback, C.; Drake, J. Evidence that amyloid beta-peptide-induced lipid peroxidation and its sequelae in Alzheimer’s disease brain contribute to neuronal death1. Neurobiol. Aging,  2002, 23(5), 655-664.
 [http://dx.doi.org/10.1016/S0197-4580(01)00340-2] [PMID:  12392766]

[94]
Esposito, L.; Raber, J.; Kekonius, L.; Yan, F.; Yu, G.Q.; Bien-Ly, N.; Puoliväli, J.; Scearce-Levie, K.; Masliah, E.; Mucke, L. Reduction in mitochondrial superoxide dismutase modulates Alzheimer’s disease-like pathology and accelerates the onset of behavioral changes in human amyloid precursor protein transgenic mice. J. Neurosci.,  2006, 26(19), 5167-5179.
 [http://dx.doi.org/10.1523/JNEUROSCI.0482-06.2006] [PMID:  16687508]

[95]
Kim, S.H.; Fountoulakis, M.; Cairns, N.; Lubec, G. Protein levels of human peroxiredoxin subtypes in brains of patients with Alzheimer’s disease and Down Syndrome. J. Neural Transm. Suppl.,  2001, (61), 223-235.
 [http://dx.doi.org/10.1007/978-3-7091-6262-0_18] [PMID:  11771746]

[96]
Krapfenbauer, K.; Engidawork, E.; Cairns, N.; Fountoulakis, M.; Lubec, G. Aberrant expression of peroxiredoxin subtypes in neurodegenerative disorders. Brain Res.,  2003, 967(1-2), 152-160.
 [http://dx.doi.org/10.1016/S0006-8993(02)04243-9] [PMID:  12650976]

[97]
Kirby, J.; Halligan, E.; Baptista, M.J.; Allen, S.; Heath, P.R.; Holden, H.; Barber, S.C.; Loynes, C.A.; Wood-Allum, C.A.; Lunec, J.; Shaw, P.J. Mutant SOD1 alters the motor neuronal transcriptome: Implications for familial ALS. Brain,  2005, 128(7), 1686-1706.
 [http://dx.doi.org/10.1093/brain/awh503] [PMID:  15872021]

[98]
Bosch, M.; Marí, M.; Herms, A.; Fernández, A.; Fajardo, A.; Kassan, A.; Giralt, A.; Colell, A.; Balgoma, D.; Barbero, E.; González-Moreno, E.; Matias, N.; Tebar, F.; Balsinde, J.; Camps, M.; Enrich, C.; Gross, S.P.; García-Ruiz, C.; Pérez-Navarro, E.; Fernández-Checa, J.C.; Pol, A. Caveolin-1 deficiency causes cholesterol-dependent mitochondrial dysfunction and apoptotic susceptibility. Curr. Biol.,  2011, 21(8), 681-686.
 [http://dx.doi.org/10.1016/j.cub.2011.03.030] [PMID:  21497090]

[99]
Anderson, S.; Bankier, A.T.; Barrell, B.G.; de Bruijn, M.H.L.; Coulson, A.R.; Drouin, J.; Eperon, I.C.; Nierlich, D.P.; Roe, B.A.; Sanger, F.; Schreier, P.H.; Smith, A.J.H.; Staden, R.; Young, I.G. Sequence and organization of the human mitochondrial genome. Nature,  1981, 290(5806), 457-465.
 [http://dx.doi.org/10.1038/290457a0] [PMID:  7219534]

[100]
Shadel, G.S.; Horvath, T.L. Mitochondrial ROS signaling in organismal homeostasis. Cell,  2015, 163(3), 560-569.
 [http://dx.doi.org/10.1016/j.cell.2015.10.001] [PMID:  26496603]

[101]
Beal, M.F. Mitochondria take center stage in aging and neurodegeneration. Ann. Neurol.,  2005, 58(4), 495-505.
 [http://dx.doi.org/10.1002/ana.20624] [PMID:  16178023]

[102]
Stuart, J.A.; Hashiguchi, K.; Wilson, D.M., III; Copeland, W.C.; Souza-Pinto, N.C.; Bohr, V.A. DNA base excision repair activities and pathway function in mitochondrial and cellular lysates from cells lacking mitochondrial DNA. Nucleic Acids Res.,  2004, 32(7), 2181-2192.
 [http://dx.doi.org/10.1093/nar/gkh533] [PMID:  15107486]

[103]
Bohr, V.A. Repair of oxidative DNA damage in nuclear and mitochondrial DNA, and some changes with aging in mammalian cells1,2 1Guest Editor: Miral Dizdaroglu 2This article is part of a series of reviews on “Oxidative DNA Damage and Repair.” The full list of papers may be found on the homepage of the journal. Free Radic. Biol. Med.,  2002, 32(9), 804-812.
 [http://dx.doi.org/10.1016/S0891-5849(02)00787-6] [PMID:  11978482]

[104]
Coskun, P.E.; Beal, M.F.; Wallace, D.C. Alzheimer’s brains harbor somatic mtDNA control-region mutations that suppress mitochondrial transcription and replication. Proc. Natl. Acad. Sci. USA,  2004, 101(29), 10726-10731.
 [http://dx.doi.org/10.1073/pnas.0403649101] [PMID:  15247418]

[105]
Hutchin, T.P.; Heath, P.R.; Pearson, R.C.A.; Sinclair, A.J. Mitochondrial DNA mutations in Alzheimer’s disease. Biochem. Biophys. Res. Commun.,  1997, 241(2), 221-225.
 [http://dx.doi.org/10.1006/bbrc.1997.7793] [PMID:  9425253]

[106]
Wiedemann, F.R.; Manfredi, G.; Mawrin, C.; Beal, M.F.; Schon, E.A. Mitochondrial DNA and respiratory chain function in spinal cords of ALS patients. J. Neurochem.,  2002, 80(4), 616-625.
 [http://dx.doi.org/10.1046/j.0022-3042.2001.00731.x] [PMID:  11841569]

[107]
Hamblet, N.S.; Ragland, B.; Ali, M.; Conyers, B.; Castora, F.J. Mutations in mitochondrial-encoded cytochromec oxidase subunits I, II, and III genes detected in Alzheimer’s disease using single-strand conformation polymorphism. Electrophoresis,  2006, 27(2), 398-408.
 [http://dx.doi.org/10.1002/elps.200500420] [PMID:  16358358]

[108]
Cardoso, S.M.; Santana, I.; Swerdlow, R.H.; Oliveira, C.R. Mitochondria dysfunction of Alzheimer’s disease cybrids enhances Aβ toxicity. J. Neurochem.,  2004, 89(6), 1417-1426.
 [http://dx.doi.org/10.1111/j.1471-4159.2004.02438.x] [PMID:  15189344]

[109]
Richter, G.; Sonnenschein, A.; Grünewald, T.; Reichmann, H.; Janetzky, B. Novel mitochondrial DNA mutations in Parkinson’s disease. J. Neural Transm. (Vienna),  2002, 109(5-6), 721-729.
 [http://dx.doi.org/10.1007/s007020200060] [PMID:  12111463]

[110]
Swerdlow, R.H.; Parks, J.K.; Davis, J.N., II; Cassarino, D.S.; Trimmer, P.A.; Currie, L.J.; Dougherty, J.; Bridges, W.S.; Bennett, J.P., Jr; Wooten, G.F.; Parker, W.D. Matrilineal inheritance of complex I dysfunction in a multigenerational Parkinson’s disease family. Ann. Neurol.,  1998, 44(6), 873-881.
 [http://dx.doi.org/10.1002/ana.410440605] [PMID:  9851431]

[111]
Krishnan, K.J.; Ratnaike, T.E.; De Gruyter, H.L.M.; Jaros, E.; Turnbull, D.M. Mitochondrial DNA deletions cause the biochemical defect observed in Alzheimer’s disease. Neurobiol. Aging,  2012, 33(9), 2210-2214.
 [http://dx.doi.org/10.1016/j.neurobiolaging.2011.08.009] [PMID:  21925769]

[112]
Murakami, T.; Nagai, M.; Miyazaki, K.; Morimoto, N.; Ohta, Y.; Kurata, T.; Takehisa, Y.; Kamiya, T.; Abe, K. Early decrease of mitochondrial DNA repair enzymes in spinal motor neurons of presymptomatic transgenic mice carrying a mutant SOD1 gene. Brain Res.,  2007, 1150, 182-189.
 [http://dx.doi.org/10.1016/j.brainres.2007.02.057] [PMID:  17434152]

[113]
Israelson, A.; Arbel, N.; Da Cruz, S.; Ilieva, H.; Yamanaka, K.; Shoshan-Barmatz, V.; Cleveland, D.W. Misfolded mutant SOD1 directly inhibits VDAC1 conductance in a mouse model of inherited ALS. Neuron,  2010, 67(4), 575-587.
 [http://dx.doi.org/10.1016/j.neuron.2010.07.019] [PMID:  20797535]

[114]
Warita, H.; Hayashi, T.; Murakami, T.; Manabe, Y.; Abe, K. Oxidative damage to mitochondrial DNA in spinal motoneurons of transgenic ALS mice. Brain Res. Mol. Brain Res.,  2001, 89(1-2), 147-152.
 [http://dx.doi.org/10.1016/S0169-328X(01)00029-8] [PMID:  11311985]

[115]
Dhaliwal, G.K.; Grewal, R.P. Mitochondrial DNA deletion mutation levels are elevated in ALS brains. Neuroreport,  2000, 11(11), 2507-2509.
 [http://dx.doi.org/10.1097/00001756-200008030-00032] [PMID:  10943712]

[116]
Tsai, F.C.; Seki, A.; Yang, H.W.; Hayer, A.; Carrasco, S.; Malmersjö, S.; Meyer, T. A polarized Ca2+, diacylglycerol and STIM1 signalling system regulates directed cell migration. Nat. Cell Biol.,  2014, 16(2), 133-144.
 [http://dx.doi.org/10.1038/ncb2906] [PMID:  24463606]

[117]
Yang, S.; Huang, X.Y. Ca2+ influx through L-type Ca2+ channels controls the trailing tail contraction in growth factor-induced fibroblast cell migration. J. Biol. Chem.,  2005, 280(29), 27130-27137.
 [http://dx.doi.org/10.1074/jbc.M501625200] [PMID:  15911622]

[118]
Hartmann, J.; Verkhratsky, A. Relations between intracellular Ca2+ stores and store-operated Ca2+ entry in primary cultured human glioblastoma cells. J. Physiol.,  1998, 513(Pt 2), 411-424.

[119]
Roos, D.; Seeger, R.; Puntel, R.; Vargas Barbosa, N. Role of calcium and mitochondria in MeHg-mediated cytotoxicity. J. Biomed. Biotechnol.,  2012, 2012, 1-15.
 [http://dx.doi.org/10.1155/2012/248764] [PMID:  22927718]

[120]
Imbert, N.; Cognard, C.; Duport, G.; Guillou, C.; Raymond, G. Abnormal calcium homeostasis in Duchenne muscular dystrophy myotubes contracting in vitro. Cell Calcium,  1995, 18(3), 177-186.
 [http://dx.doi.org/10.1016/0143-4160(95)90062-4] [PMID:  8529258]

[121]
Xiong, J.; Camello, P.J.; Verkhratsky, A.; Toescu, E.C. Mitochondrial polarisation status and Ca2+ signalling in rat cerebellar granule neurones aged in vitro. Neurobiol. Aging,  2004, 25(3), 349-359.
 [http://dx.doi.org/10.1016/S0197-4580(03)00123-4] [PMID:  15123341]

[122]
Tang, S.; Wang, X.; Shen, Q.; Yang, X.; Yu, C.; Cai, C.; Cai, G.; Meng, X.; Zou, F. Mitochondrial Ca2+ uniporter is critical for store-operated Ca2+ entry-dependent breast cancer cell migration. Biochem. Biophys. Res. Commun.,  2015, 458(1), 186-193.
 [http://dx.doi.org/10.1016/j.bbrc.2015.01.092] [PMID:  25640838]

[123]
Panov, A.V.; Lund, S.; Greenamyre, J.T. Ca2+-induced permeability transition in human lymphoblastoid cell mitochondria from normal and Huntington?s disease individuals. Mol. Cell. Biochem.,  2005, 269(1), 143-152.
 [http://dx.doi.org/10.1007/s11010-005-3454-9] [PMID:  15786727]

[124]
Quintanilla, R.A.; Johnson, G.V.W. Role of mitochondrial dysfunction in the pathogenesis of Huntington’s disease. Brain Res. Bull.,  2009, 80(4-5), 242-247.
 [http://dx.doi.org/10.1016/j.brainresbull.2009.07.010] [PMID:  19622387]

[125]
Jaiswal, M.K.; Zech, W.D.; Goos, M.; Leutbecher, C.; Ferri, A.; Zippelius, A.; Carrì, M.T.; Nau, R.; Keller, B.U. Impairment of mitochondrial calcium handling in a mtSOD1 cell culture model of motoneuron disease. BMC Neurosci.,  2009, 10(1), 64.
 [http://dx.doi.org/10.1186/1471-2202-10-64] [PMID:  19545440]

[126]
Sheehan, J.P.; Swerdlow, R.H.; Miller, S.W.; Davis, R.E.; Parks, J.K.; Parker, W.D.; Tuttle, J.B. Calcium homeostasis and reactive oxygen species production in cells transformed by mitochondria from individuals with sporadic Alzheimer’s disease. J. Neurosci.,  1997, 17(12), 4612-4622.
 [http://dx.doi.org/10.1523/JNEUROSCI.17-12-04612.1997] [PMID:  9169522]

[127]
Du, H.; Guo, L.; Zhang, W.; Rydzewska, M.; Yan, S. Cyclophilin D deficiency improves mitochondrial function and learning/memory in aging Alzheimer disease mouse model. Neurobiol. Aging,  2011, 32(3), 398-406.
 [http://dx.doi.org/10.1016/j.neurobiolaging.2009.03.003] [PMID:  19362755]

[128]
Alevriadou, B.R.; Patel, A.; Noble, M.; Ghosh, S.; Gohil, V.M.; Stathopulos, P.B.; Madesh, M. Molecular nature and physiological role of the mitochondrial calcium uniporter channel. Am. J. Physiol. Cell Physiol.,  2021, 320(4), C465-C482.
 [http://dx.doi.org/10.1152/ajpcell.00502.2020] [PMID:  33296287]

[129]
Petersén, Å.; Castilho, R.F.; Hansson, O.; Wieloch, T.; Brundin, P. Oxidative stress, mitochondrial permeability transition and activation of caspases in calcium ionophore A23187-induced death of cultured striatal neurons. Brain Res.,  2000, 857(1-2), 20-29.
 [http://dx.doi.org/10.1016/S0006-8993(99)02320-3] [PMID:  10700549]

[130]
Halestrap, A.P. Calcium, mitochondria and reperfusion injury: A pore way to die. Biochem. Soc. Trans.,  2006, 34(2), 232-237.
 [http://dx.doi.org/10.1042/BST0340232] [PMID:  16545083]

[131]
Halestrap, A.P.; Griffiths, E.J.; Connern, C.P. Mitochondrial calcium handling and oxidative stress. Biochem. Soc. Trans.,  1993, 21(2), 353-358.
 [http://dx.doi.org/10.1042/bst0210353] [PMID:  8359495]

[132]
Kantrow, S.P.; Tatro, L.G.; Piantadosi, C.A. Oxidative stress and adenine nucleotide control of mitochondrial permeability transition. Free Radic. Biol. Med.,  2000, 28(2), 251-260.
 [http://dx.doi.org/10.1016/S0891-5849(99)00238-5] [PMID:  11281292]

[133]
Leung, A.W.C.; Halestrap, A.P. Recent progress in elucidating the molecular mechanism of the mitochondrial permeability transition pore. Biochim. Biophys. Acta Bioenerg.,  2008, 1777(7-8), 946-952.
 [http://dx.doi.org/10.1016/j.bbabio.2008.03.009] [PMID:  18407825]

[134]
Du, H.; Yan, S.S. Mitochondrial permeability transition pore in Alzheimer’s disease: Cyclophilin D and amyloid beta. Biochim. Biophys. Acta Mol. Basis Dis.,  2010, 1802(1), 198-204.
 [http://dx.doi.org/10.1016/j.bbadis.2009.07.005] [PMID:  19616093]

[135]
Brustovetsky, N.; Brustovetsky, T.; Purl, K.J.; Capano, M.; Crompton, M.; Dubinsky, J.M. Increased susceptibility of striatal mitochondria to calcium-induced permeability transition. J. Neurosci.,  2003, 23(12), 4858-4867.
 [http://dx.doi.org/10.1523/JNEUROSCI.23-12-04858.2003] [PMID:  12832508]

[136]
Xu, W.; Marseglia, A.; Ferrari, C.; Wang, H.X. Alzheimer’s disease: A clinical perspective. Neurodegener. Dis., 2013.
 [http://dx.doi.org/10.5772/54539]

[137]
Pathak, D.; Berthet, A.; Nakamura, K. Energy failure. Ann. Neurol.,  2013, 74(4), 506-516.
 [http://dx.doi.org/10.1002/ana.24014] [PMID:  24038413]

[138]
Sun, N.; Youle, R.J.; Finkel, T. The mitochondrial basis of aging. Mol. Cell,  2016, 61(5), 654-666.
 [http://dx.doi.org/10.1016/j.molcel.2016.01.028] [PMID:  26942670]

[139]
Zhao, X.Y.; Lu, M.H.; Yuan, D.J.; Xu, D.E.; Yao, P.P.; Ji, W.L.; Chen, H.; Liu, W.L.; Yan, C.X.; Xia, Y.Y.; Li, S.; Tao, J.; Ma, Q.H. Mitochondrial dysfunction in neural injury. Front. Neurosci.,  2019, 13, 30.
 [http://dx.doi.org/10.3389/fnins.2019.00030] [PMID:  30778282]

[140]
Fricker, M.; Tolkovsky, A.M.; Borutaite, V.; Coleman, M.; Brown, G.C. Neuronal cell death. Physiol. Rev.,  2018, 98(2), 813-880.
 [http://dx.doi.org/10.1152/physrev.00011.2017] [PMID:  29488822]

[141]
Johri, A.; Beal, M.F. Mitochondrial dysfunction in neurodegenerative diseases. J. Pharmacol. Exp. Ther.,  2012, 342(3), 619-630.
 [http://dx.doi.org/10.1124/jpet.112.192138] [PMID:  22700435]

[142]
Hoekstra, J.G.; Montine, K.S.; Zhang, J.; Montine, T.J. Mitochondrial therapeutics in Alzheimer’s disease and Parkinson’s disease. Alzheimers Res. Ther.,  2011, 3(3), 21.
 [http://dx.doi.org/10.1186/alzrt83] [PMID:  21722346]

[143]
Monzio Compagnoni, G.; Di Fonzo, A.; Corti, S.; Comi, G.P.; Bresolin, N.; Masliah, E. The role of mitochondria in neurodegenerative diseases: The lesson from Alzheimer’s disease and Parkinson’s disease. Mol. Neurobiol.,  2020, 57(7), 2959-2980.
 [http://dx.doi.org/10.1007/s12035-020-01926-1] [PMID:  32445085]

[144]
Hroudová, J.; Singh, N.; Fišar, Z. Mitochondrial dysfunctions in neurodegenerative diseases: Relevance to Alzheimer’s disease. BioMed Res. Int.,  2014, 2014, 1-9.
 [http://dx.doi.org/10.1155/2014/175062] [PMID:  24900954]

[145]
Sims, N.R.; Muyderman, H. Mitochondria, oxidative metabolism and cell death in stroke. Biochim. Biophys. Acta Mol. Basis Dis.,  2010, 1802(1), 80-91.
 [http://dx.doi.org/10.1016/j.bbadis.2009.09.003] [PMID:  19751827]

[146]
Kish, S.J.; Bergeron, C.; Rajput, A.; Dozic, S.; Mastrogiacomo, F.; Chang, L.J.; Wilson, J.M.; DiStefano, L.M.; Nobrega, J.N. Brain cytochrome oxidase in Alzheimer’s disease. J. Neurochem.,  1992, 59(2), 776-779.
 [http://dx.doi.org/10.1111/j.1471-4159.1992.tb09439.x] [PMID:  1321237]

[147]
Maurer, I.; Zierz, S.; Möller, H.J. A selective defect of cytochrome c oxidase is present in brain of Alzheimer disease patients. Neurobiol. Aging,  2000, 21(3), 455-462.
 [http://dx.doi.org/10.1016/S0197-4580(00)00112-3] [PMID:  10858595]

[148]
Siasos, G.; Tsigkou, V.; Kosmopoulos, M.; Theodosiadis, D.; Simantiris, S.; Tagkou, N.M.; Tsimpiktsioglou, A.; Stampouloglou, P.K.; Oikonomou, E.; Mourouzis, K.; Philippou, A.; Vavuranakis, M.; Stefanadis, C.; Tousoulis, D.; Papavassiliou, A.G. Mitochondria and cardiovascular diseases—from pathophysiology to treatment. Ann. Transl. Med.,  2018, 6(12), 256.
 [http://dx.doi.org/10.21037/atm.2018.06.21] [PMID:  30069458]

[149]
Moreira, O.C.; Estébanez, B.; Martínez-Florez, S.; Paz, J.A.; Cuevas, M.J.; González-Gallego, J. Mitochondrial function and mitophagy in the elderly: Effects of exercise. Oxid. Med. Cell. Longev.,  2017, 2017, 1-13.
 [http://dx.doi.org/10.1155/2017/2012798] [PMID:  28900532]

[150]
Chen, J.Q.; Cammarata, P.R.; Baines, C.P.; Yager, J.D. Regulation of mitochondrial respiratory chain biogenesis by estrogens/estrogen receptors and physiological, pathological and pharmacological implications. Biochim. Biophys. Acta Mol. Cell Res.,  2009, 1793(10), 1540-1570.
 [http://dx.doi.org/10.1016/j.bbamcr.2009.06.001] [PMID:  19559056]

[151]
Prossnitz, E.R.; Barton, M. The G-protein-coupled estrogen receptor GPER in health and disease. Nat. Rev. Endocrinol.,  2011, 7(12), 715-726.
 [http://dx.doi.org/10.1038/nrendo.2011.122] [PMID:  21844907]

[152]
Brann, D.W.; Dhandapani, K.; Wakade, C.; Mahesh, V.B.; Khan, M.M. Neurotrophic and neuroprotective actions of estrogen: Basic mechanisms and clinical implications. Steroids,  2007, 72(5), 381-405.
 [http://dx.doi.org/10.1016/j.steroids.2007.02.003] [PMID:  17379265]

[153]
Lejri, I.; Grimm, A.; Eckert, A. Mitochondria, estrogen and female brain aging. Front. Aging Neurosci.,  2018, 10, 124.
 [http://dx.doi.org/10.3389/fnagi.2018.00124] [PMID:  29755342]

[154]
Fetisova, E.; Chernyak, B.; Korshunova, G.; Muntyan, M.; Skulachev, V. Mitochondria-targeted Antioxidants as a Prospective Therapeutic Strategy for Multiple Sclerosis. Curr. Med. Chem.,  2017, 24(19), 2086-2114.
 [PMID:  28302008]

[155]
Macdonald, R.; Barnes, K.; Hastings, C.; Mortiboys, H. Mitochondrial abnormalities in Parkinson’s disease and Alzheimer’s disease: Can mitochondria be targeted therapeutically? Biochem. Soc. Trans.,  2018, 46(4), 891-909.
 [http://dx.doi.org/10.1042/BST20170501] [PMID:  30026371]

[156]
Fão, L.; Rego, A.C. Mitochondrial and redox-based therapeutic strategies in Huntington’s disease. Antioxid. Redox Signal.,  2021, 34(8), 650-673.
 [http://dx.doi.org/10.1089/ars.2019.8004] [PMID:  32498555]

[157]
Van Giau, V.; An, S.S.A.; Hulme, J.P. Mitochondrial therapeutic interventions in Alzheimer’s disease. J. Neurol. Sci.,  2018, 395, 62-70.
 [http://dx.doi.org/10.1016/j.jns.2018.09.033] [PMID:  30292965]

[158]
Zinovkin, R.A.; Zamyatnin, A.A. Mitochondria-targeted drugs. Curr. Mol. Pharmacol.,  2019, 12(3), 202-214.
 [http://dx.doi.org/10.2174/1874467212666181127151059] [PMID:  30479224]

[159]
Burns, R.J.; Smith, R.A.J.; Murphy, M.P. Synthesis and characterization of thiobutyltriphenylphosphonium bromide, a novel thiol reagent targeted to the mitochondrial matrix. Arch. Biochem. Biophys.,  1995, 322(1), 60-68.
 [http://dx.doi.org/10.1006/abbi.1995.1436] [PMID:  7574695]

[160]
Adam-Vizi, V.; Chinopoulos, C. Bioenergetics and the formation of mitochondrial reactive oxygen species. Trends Pharmacol. Sci.,  2006, 27(12), 639-645.
 [http://dx.doi.org/10.1016/j.tips.2006.10.005] [PMID:  17056127]

[161]
Zorova, L.D.; Popkov, V.A.; Plotnikov, E.Y.; Silachev, D.N.; Pevzner, I.B.; Jankauskas, S.S.; Babenko, V.A.; Zorov, S.D.; Balakireva, A.V.; Juhaszova, M.; Sollott, S.J.; Zorov, D.B. Mitochondrial membrane potential. Anal. Biochem.,  2018, 552, 50-59.
 [http://dx.doi.org/10.1016/j.ab.2017.07.009] [PMID:  28711444]

[162]
Mileykovskaya, E.; Dowhan, W. Cardiolipin-dependent formation of mitochondrial respiratory supercomplexes. Chem. Phys. Lipids,  2014, 179, 42-48.
 [http://dx.doi.org/10.1016/j.chemphyslip.2013.10.012] [PMID:  24220496]

[163]
Kang, Y.; Fielden, L.F.; Stojanovski, D. Mitochondrial protein transport in health and disease. Semin. Cell Dev. Biol.,  2018, 76, 142-153.
 [http://dx.doi.org/10.1016/j.semcdb.2017.07.028] [PMID:  28765093]

[164]
Korshunov, S.S.; Skulachev, V.P.; Starkov, A.A. High protonic potential actuates a mechanism of production of reactive oxygen species in mitochondria. FEBS Lett.,  1997, 416(1), 15-18.
 [http://dx.doi.org/10.1016/S0014-5793(97)01159-9] [PMID:  9369223]

[165]
Antonenko, Y.N.; Avetisyan, A.V.; Bakeeva, L.E.; Chernyak, B.V.; Chertkov, V.A.; Domnina, L.V.; Ivanova, O.Y.; Izyumov, D.S.; Khailova, L.S.; Klishin, S.S.; Korshunova, G.A.; Lyamzaev, K.G.; Muntyan, M.S.; Nepryakhina, O.K.; Pashkovskaya, A.A.; Pletjushkina, O.Y.; Pustovidko, A.V.; Roginsky, V.A.; Rokitskaya, T.I.; Ruuge, E.K.; Saprunova, V.B.; Severina, I.I.; Simonyan, R.A.; Skulachev, I.V.; Skulachev, M.V.; Sumbatyan, N.V.; Sviryaeva, I.V.; Tashlitsky, V.N.; Vassiliev, J.M.; Vyssokikh, M.Y.; Yaguzhinsky, L.S.; Zamyatnin, A.A., Jr; Skulachev, V.P. Mitochondria-targeted plastoquinone derivatives as tools to interrupt execution of the aging program. 1. Cationic plastoquinone derivatives: Synthesis and in vitro studies. Biochemistry (Mosc.),  2008, 73(12), 1273-1287.
 [http://dx.doi.org/10.1134/S0006297908120018]

[166]
Fink, B.D.; Herlein, J.A.; Yorek, M.A.; Fenner, A.M.; Kerns, R.J.; Sivitz, W.I. Bioenergetic effects of mitochondrial-targeted coenzyme Q analogs in endothelial cells. J. Pharmacol. Exp. Ther.,  2012, 342(3), 709-719.
 [http://dx.doi.org/10.1124/jpet.112.195586] [PMID:  22661629]

[167]
Nickel, A.; Kohlhaas, M.; Maack, C. Mitochondrial reactive oxygen species production and elimination. J. Mol. Cell. Cardiol.,  2014, 73, 26-33.
 [http://dx.doi.org/10.1016/j.yjmcc.2014.03.011] [PMID:  24657720]

[168]
Chiurchiù, V.; Orlacchio, A.; Maccarrone, M. Is modulation of oxidative stress an answer? The state of the art of redox therapeutic actions in neurodegenerative diseases. Oxid. Med. Cell. Longev.,  2016, 2016, 1-11.
 [http://dx.doi.org/10.1155/2016/7909380] [PMID:  26881039]

[169]
Bravo, L. Polyphenols: Chemistry, dietary sources, metabolism, and nutritional significance. Nutr. Rev.,  1998, 56(11), 317-333.
 [http://dx.doi.org/10.1111/j.1753-4887.1998.tb01670.x] [PMID:  9838798]

[170]
Rudra, A.; Arvind, I.; Mehra, R. Polyphenols: Types, sources and therapeutic applications. Int. J. Home Sci.,  2021, 7(3), 69-75.
 [http://dx.doi.org/10.22271/23957476.2021.v7.i3a.1182]

[171]
Leri, M.; Scuto, M.; Ontario, M.L.; Calabrese, V.; Calabrese, E.J.; Bucciantini, M.; Stefani, M. Healthy effects of plant polyphenols: Molecular mechanisms. Int. J. Mol. Sci.,  2020, 21(4), 1250.
 [http://dx.doi.org/10.3390/ijms21041250] [PMID:  32070025]

[172]
Losada-Barreiro, S.; Bravo-Díaz, C. Free radicals and polyphenols: The redox chemistry of neurodegenerative diseases. Eur. J. Med. Chem.,  2017, 133, 379-402.
 [http://dx.doi.org/10.1016/j.ejmech.2017.03.061] [PMID:  28415050]

[173]
Miquel, S.; Champ, C.; Day, J.; Aarts, E.; Bahr, B.A.; Bakker, M.; Bánáti, D.; Calabrese, V.; Cederholm, T.; Cryan, J.; Dye, L.; Farrimond, J.A.; Korosi, A.; Layé, S.; Maudsley, S.; Milenkovic, D.; Mohajeri, M.H.; Sijben, J.; Solomon, A.; Spencer, J.P.E.; Thuret, S.; Vanden, B.W.; Vauzour, D.; Vellas, B.; Wesnes, K.; Willatts, P.; Wittenberg, R.; Geurts, L. Poor cognitive ageing: Vulnerabilities, mechanisms and the impact of nutritional interventions. Ageing Res. Rev.,  2018, 42, 40-55.
 [http://dx.doi.org/10.1016/j.arr.2017.12.004] [PMID:  29248758]

[174]
Franco, R.; Navarro, G.; Martínez-Pinilla, E. Plant-derived compounds, vitagens, vitagenes and mitochondrial function. PharmaNutrition,  2022, 19, 100287.
 [http://dx.doi.org/10.1016/j.phanu.2021.100287]

[175]
Trovato Salinaro, A.; Cornelius, C.; Koverech, G.; Koverech, A.; Scuto, M.; Lodato, F.; Fronte, V.; Muccilli, V.; Reibaldi, M.; Longo, A.; Uva, M.G.; Calabrese, V. Cellular stress response, redox status, and vitagenes in glaucoma: A systemic oxidant disorder linked to Alzheimer’s disease. Front. Pharmacol.,  2014, 5, 129.
 [http://dx.doi.org/10.3389/fphar.2014.00129] [PMID:  24936186]

[176]
Wakabayashi, N.; Itoh, K.; Wakabayashi, J.; Motohashi, H.; Noda, S.; Takahashi, S.; Imakado, S.; Kotsuji, T.; Otsuka, F.; Roop, D.R.; Harada, T.; Engel, J.D.; Yamamoto, M. Keap1-null mutation leads to postnatal lethality due to constitutive Nrf2 activation. Nat. Genet.,  2003, 35(3), 238-245.
 [http://dx.doi.org/10.1038/ng1248] [PMID:  14517554]

[177]
Calabrese, E.J.; Kozumbo, W.J. The hormetic dose-response mechanism: Nrf2 activation. Pharmacol. Res.,  2021, 167, 105526.
 [http://dx.doi.org/10.1016/j.phrs.2021.105526] [PMID:  33667690]

[178]
Calabrese, E.J. Hormesis: Principles and applications. Homeopathy,  2015, 104(2), 69-82.

[179]
Mattson, M.P. Hormesis and disease resistance: Activation of cellular stress response pathways. Hum. Exp. Toxicol.,  2008, 27(2), 155-162.
 [http://dx.doi.org/10.1177/0960327107083417] [PMID:  18480142]

[180]
Cornelius, C.; Trovato, S.A.; Scuto, M.; Fronte, V.; Cambria, M.T.; Pennisi, M.; Bella, R.; Milone, P.; Graziano, A.; Crupi, R.; Cuzzocrea, S.; Pennisi, G.; Calabrese, V. Cellular stress response, sirtuins and UCP proteins in Alzheimer disease: Role of vitagenes. Immun. Ageing,  2013, 10(1), 41.

[181]
Mancuso, C.; Santangelo, R.; Calabrese, V. The heme oxygenase/biliverdin reductase system: A potential drug target in Alzheimer’s disease. J. Biol. Regul. Homeost. Agents,  2013, 27(2)(Suppl.), 75-87.
 [PMID:  24813317]

[182]
Pilipenko, V.; Narbute, K.; Amara, I.; Trovato, A.; Scuto, M.; Pupure, J.; Jansone, B.; Poikans, J.; Bisenieks, E.; Klusa, V.; Calabrese, V. GABA‐containing compound gammapyrone protects against brain impairments in Alzheimer’s disease model male rats and prevents mitochondrial dysfunction in cell culture. J. Neurosci. Res.,  2019, 97(6), 708-726.
 [http://dx.doi.org/10.1002/jnr.24396] [PMID:  30742328]

[183]
Crompton, M.; Ellinger, H.; Costi, A. Inhibition by cyclosporin A of a Ca2+-dependent pore in heart mitochondria activated by inorganic phosphate and oxidative stress. Biochem. J.,  1988, 255(1), 357-360.
 [PMID:  3196322]

[184]
Briston, T.; Selwood, D.L.; Szabadkai, G.; Duchen, M.R. Mitochondrial permeability transition: A molecular lesion with multiple drug targets. Trends Pharmacol. Sci.,  2019, 40(1), 50-70.
 [http://dx.doi.org/10.1016/j.tips.2018.11.004] [PMID:  30527591]

[185]
Amanakis, G.; Murphy, E.; Cyclophilin, D.; Cyclophilin, D. An integrator of mitochondrial function. Front. Physiol.,  2020, 11, 595.
 [http://dx.doi.org/10.3389/fphys.2020.00595] [PMID:  32625108]

[186]
Baines, C.P.; Kaiser, R.A.; Purcell, N.H.; Blair, N.S.; Osinska, H.; Hambleton, M.A.; Brunskill, E.W.; Sayen, M.R.; Gottlieb, R.A.; Dorn, G.W., II; Robbins, J.; Molkentin, J.D. Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death. Nature,  2005, 434(7033), 658-662.
 [http://dx.doi.org/10.1038/nature03434] [PMID:  15800627]

[187]
Baines, C.P.; Gutiérrez-Aguilar, M. The still uncertain identity of the channel-forming unit(s) of the mitochondrial permeability transition pore. Cell Calcium,  2018, 73, 121-130.
 [http://dx.doi.org/10.1016/j.ceca.2018.05.003] [PMID:  29793100]

[188]
Kalani, K.; Yan, S.F.; Yan, S.S. Mitochondrial permeability transition pore: A potential drug target for neurodegeneration. Drug Discov. Today,  2018, 23(12), 1983-1989.
 [http://dx.doi.org/10.1016/j.drudis.2018.08.001] [PMID:  30081095]

[189]
Du, H.; Guo, L.; Fang, F.; Chen, D.; Sosunov, A. A.; M McKhann, G.; Yan, Y.; Wang, C.; Zhang, H.; Molkentin, J.D.; Gunn-Moore, F.J.; Vonsattel, J.P.; Arancio, O.; Chen, J.X.; Yan, S.D. Cyclophilin D deficiency attenuates mitochondrial and neuronal perturbation and ameliorates learning and memory in Alzheimer’s disease. Nat. Med.,  2008, 14(10), 1097-1105.
 [http://dx.doi.org/10.1038/nm.1868] [PMID:  18806802]

[190]
Thomas, B.; Banerjee, R.; Starkova, N.N.; Zhang, S.F.; Calingasan, N.Y.; Yang, L.; Wille, E.; Lorenzo, B.J.; Ho, D.J.; Beal, M.F.; Starkov, A. Mitochondrial permeability transition pore component cyclophilin D distinguishes nigrostriatal dopaminergic death paradigms in the MPTP mouse model of Parkinson’s disease. Antioxid. Redox Signal.,  2012, 16(9), 855-868.
 [http://dx.doi.org/10.1089/ars.2010.3849] [PMID:  21529244]

[191]
Brouhard, B.H.; Graham, R.M. Cyclosporine: Mechanisms of action and toxicity. Cleve. Clin. J. Med.,  1994, 61(4), 308-313.
 [http://dx.doi.org/10.3949/ccjm.61.4.308] [PMID:  7923750]

[192]
Valasani, K.R.; Chaney, M.O.; Day, V.W. ShiDu Yan, S. S. Acetylcholinesterase inhibitors: Structure based design, synthesis, pharmacophore modeling, and virtual screening. J. Chem. Inf. Model.,  2013, 53(8), 2033-2046.
 [http://dx.doi.org/10.1021/ci400196z] [PMID:  23777291]

[193]
Ahmed-Belkacem, A.; Colliandre, L.; Ahnou, N.; Nevers, Q.; Gelin, M.; Bessin, Y.; Brillet, R.; Cala, O.; Douguet, D.; Bourguet, W.; Krimm, I.; Pawlotsky, J.M.; Guichou, J.F. Fragment-based discovery of a new family of non-peptidic small-molecule cyclophilin inhibitors with potent antiviral activities. Nat. Commun.,  2016, 7(1), 12777.
 [http://dx.doi.org/10.1038/ncomms12777] [PMID:  27652979]

[194]
Guo, H.; Wang, F.; Yu, K.; Chen, J.; Bai, D.; Chen, K.; Shen, X.; Jiang, H. Novel cyclophilin D inhibitors derived from quinoxaline exhibit highly inhibitory activity against rat mitochondrial swelling and Ca2+ uptake/release. Acta Pharmacol. Sin.,  2005, 26(10), 1201-1211.
 [http://dx.doi.org/10.1111/j.1745-7254.2005.00189.x] [PMID:  16174436]

[195]
Hudry, E.; Vandenberghe, L.H. Therapeutic AAV gene transfer to the nervous system: A clinical reality. Neuron,  2019, 101(5), 839-862.
 [http://dx.doi.org/10.1016/j.neuron.2019.02.017] [PMID:  30844402]

[196]
Weinberg, M.S.; Samulski, R.J.; McCown, T.J. Adeno-associated virus (AAV) gene therapy for neurological disease. Neuropharmacology,  2013, 69, 82-88.
 [http://dx.doi.org/10.1016/j.neuropharm.2012.03.004] [PMID:  22465202]

[197]
Chen, W.; Hu, Y.; Ju, D. Gene therapy for neurodegenerative disorders: Advances, insights and prospects. Acta Pharm. Sin. B,  2020, 10(8), 1347-1359.
 [http://dx.doi.org/10.1016/j.apsb.2020.01.015] [PMID:  32963936]

[198]
Rafii, M.S.; Tuszynski, M.H.; Thomas, R.G.; Barba, D.; Brewer, J.B.; Rissman, R.A.; Siffert, J.; Aisen, P.S. Adeno-associated viral vector (Serotype 2)–nerve growth factor for patients with Alzheimer disease. JAMA Neurol.,  2018, 75(7), 834-841.
 [http://dx.doi.org/10.1001/jamaneurol.2018.0233] [PMID:  29582053]

[199]
Nilsson, P.; Iwata, N.; Muramatsu, S.; Tjernberg, L.O.; Winblad, B.; Saido, T.C. Gene therapy in Alzheimer’s disease - potential for disease modification. J. Cell. Mol. Med.,  2010, 14(4), 741-757.
 [http://dx.doi.org/10.1111/j.1582-4934.2010.01038.x] [PMID:  20158567]

[200]
Choong, C.J.; Mochizuki, H. Gene therapy targeting mitochondrial pathway in Parkinson’s disease. J. Neural Transm.,  2017, 124(2), 193-207.

[201]
Zhang, L.; Reyes, A.; Wang, X. The role of mitochondria-targeted antioxidant MitoQ in neurodegenerative disease. Mol. Cell. Ther.,  2018, 1-8.

[202]
Ross, M.F.; Kelso, G.F.; Blaikie, F.H.; James, A.M.; Cochemé, H.M.; Filipovska, A.; Da Ros, T.; Hurd, T.R.; Smith, R.A.J.; Murphy, M.P. Lipophilic triphenylphosphonium cations as tools in mitochondrial bioenergetics and free radical biology. Biochemistry (Mosc.),  2005, 70(2), 222-230.
 [http://dx.doi.org/10.1007/s10541-005-0104-5] [PMID:  15807662]

[203]
Kelso, G.F.; Porteous, C.M.; Coulter, C.V.; Hughes, G.; Porteous, W.K.; Ledgerwood, E.C.; Smith, R.A.J.; Murphy, M.P. Selective targeting of a redox-active ubiquinone to mitochondria within cells: Antioxidant and antiapoptotic properties. J. Biol. Chem.,  2001, 276(7), 4588-4596.
 [http://dx.doi.org/10.1074/jbc.M009093200] [PMID:  11092892]

[204]
Oyewole, A.O.; Birch-Machin, M.A. Mitochondria‐targeted antioxidants. FASEB J.,  2015, 29(12), 4766-4771.
 [http://dx.doi.org/10.1096/fj.15-275404] [PMID:  26253366]

[205]
Shinn, L.J.; Lagalwar, S. Treating neurodegenerative disease with antioxidants: Efficacy of the bioactive phenol resveratrol and mitochondrial-targeted MitoQ and SkQ. Antioxidants,  2021, 10(4)

[206]
Solesio, M.E.; Prime, T.A.; Logan, A.; Murphy, M.P.; del Mar Arroyo-Jimenez, M.; Jordán, J.; Galindo, M.F. The mitochondria-targeted anti-oxidant MitoQ reduces aspects of mitochondrial fission in the 6-OHDA cell model of Parkinson’s disease. Biochim. Biophys. Acta Mol. Basis Dis.,  2013, 1832(1), 174-182.
 [http://dx.doi.org/10.1016/j.bbadis.2012.07.009] [PMID:  22846607]

[207]
Ghosh, A.; Chandran, K.; Kalivendi, S.V.; Joseph, J.; Antholine, W.E.; Hillard, C.J.; Kanthasamy, A.; Kanthasamy, A.; Kalyanaraman, B. Neuroprotection by a mitochondria-targeted drug in a Parkinson’s disease model. Free Radic. Biol. Med.,  2010, 49(11), 1674-1684.
 [http://dx.doi.org/10.1016/j.freeradbiomed.2010.08.028] [PMID:  20828611]

[208]
McManus, M.J.; Murphy, M.P.; Franklin, J.L. The mitochondria-targeted antioxidant MitoQ prevents loss of spatial memory retention and early neuropathology in a transgenic mouse model of Alzheimer’s disease. J. Neurosci.,  2011, 31(44), 15703-15715.
 [http://dx.doi.org/10.1523/JNEUROSCI.0552-11.2011] [PMID:  22049413]

[209]
Gane, E.J.; Weilert, F.; Orr, D.W.; Keogh, G.F.; Gibson, M.; Lockhart, M.M.; Frampton, C.M.; Taylor, K.M.; Smith, R.A.; Murphy, M.P. The mitochondria-targeted anti-oxidant mitoquinone decreases liver damage in a phase II study of hepatitis C patients. Liver Int.,  2010, 30(7), 1019-1026.

[210]
Ulatowski, L.M.; Manor, D. Vitamin E and neurodegeneration. Neurobiol. Dis.,  2015, 84, 78-83.
 [http://dx.doi.org/10.1016/j.nbd.2015.04.002] [PMID:  25913028]

[211]
Sokol, R.J. Vitamin E deficiency and neurologic disease. Annu. Rev. Nutr.,  1988, 8(1), 351-373.
 [http://dx.doi.org/10.1146/annurev.nu.08.070188.002031] [PMID:  3060170]

[212]
Bourre, J.M.; Clement, M. Kinetics of rat peripheral nerve, forebrain and cerebellum α-tocopherol depletion: Comparison with different organs. J. Nutr.,  1991, 121(8), 1204-1207.
 [http://dx.doi.org/10.1093/jn/121.8.1204] [PMID:  1861168]

[213]
Gohil, K.; Oommen, S.; Quach, H.T.; Vasu, V.T.; Aung, H.H.; Schock, B.; Cross, C.E.; Vatassery, G.T. Mice lacking α-tocopherol transfer protein gene have severe α-tocopherol deficiency in multiple regions of the central nervous system. Brain Res.,  2008, 1201, 167-176.
 [http://dx.doi.org/10.1016/j.brainres.2008.01.044] [PMID:  18299118]

[214]
Oppedisano, F.; Maiuolo, J.; Gliozzi, M.; Musolino, V.; Carresi, C.; Nucera, S.; Scicchitano, M.; Scarano, F.; Bosco, F.; Macrì, R.; Ruga, S.; Zito, M.C.; Palma, E.; Muscoli, C.; Mollace, V. The potential for natural antioxidant supplementation in the early stages of neurodegenerative disorders. Int. J. Mol. Sci.,  2020, 21(7), 2618.
 [http://dx.doi.org/10.3390/ijms21072618] [PMID:  32283806]

[215]
Khanna, S.; Parinandi, N.L.; Kotha, S.R.; Roy, S.; Rink, C.; Bibus, D.; Sen, C.K. Nanomolar vitamin E α-tocotrienol inhibits glutamate-induced activation of phospholipase A 2 and causes neuroprotection. J. Neurochem.,  2010, 112(5), 1249-1260.
 [http://dx.doi.org/10.1111/j.1471-4159.2009.06550.x] [PMID:  20028458]

[216]
Schirinzi, T.; Martella, G.; Imbriani, P.; Di Lazzaro, G.; Franco, D.; Colona, V.L.; Alwardat, M.; Sinibaldi, S.P.; Mercuri, N.B.; Pierantozzi, M.; Pisani, A. Dietary vitamin E as a protective factor for Parkinson’s disease: Clinical and experimental evidence. Front. Neurol.,  2019, 10, 148.
 [http://dx.doi.org/10.3389/fneur.2019.00148] [PMID:  30863359]

[217]
Etminan, M.; Gill, S.S.; Samii, A. Intake of vitamin E, vitamin C, and carotenoids and the risk of Parkinson’s disease: A meta-analysis. Lancet Neurol.,  2005, 4(6), 362-365.
 [http://dx.doi.org/10.1016/S1474-4422(05)70097-1] [PMID:  15907740]

[218]
Oliver, D.M.A.; Reddy, P.H. Small molecules as therapeutic drugs for Alzheimer’s disease. Mol. Cell. Neurosci.,  2019, 96, 47-62.
 [http://dx.doi.org/10.1016/j.mcn.2019.03.001] [PMID:  30877034]

[219]
Jin, H.; Kanthasamy, A.; Ghosh, A.; Anantharam, V.; Kalyanaraman, B.; Kanthasamy, A.G. Mitochondria-targeted antioxidants for treatment of Parkinson’s disease: Preclinical and clinical outcomes. Biochim. Biophys. Acta Mol. Basis Dis.,  2014, 1842(8), 1282-1294.
 [http://dx.doi.org/10.1016/j.bbadis.2013.09.007] [PMID:  24060637]

[220]
Poeggeler, B.; Durand, G.; Polidori, A.; Pappolla, M.A.; Vega-Naredo, I.; Coto-Montes, A.; Böker, J.; Hardeland, R.; Pucci, B. Mitochondrial medicine: Neuroprotection and life extension by the new amphiphilic nitrone LPBNAH1 acting as a highly potent antioxidant agent. J. Neurochem.,  2005, 95(4), 962-973.
 [http://dx.doi.org/10.1111/j.1471-4159.2005.03425.x] [PMID:  16135084]

[221]
Bachurin, S.; Bukatina, E.; Lermontova, N.; Tkachenko, S.; Afanasiev, A.; Grigoriev, V.; Grigorieva, I.; Ivanov, Y.U.; Sablin, S.; Zefirov, N. Antihistamine agent Dimebon as a novel neuroprotector and a cognition enhancer. Ann. N. Y. Acad. Sci.,  2001, 939(1), 425-435.
 [http://dx.doi.org/10.1111/j.1749-6632.2001.tb03654.x] [PMID:  11462798]

[222]
Doody, R.S.; Gavrilova, S.I.; Sano, M.; Thomas, R.G.; Aisen, P.S.; Bachurin, S.O.; Seely, L.; Hung, D. Effect of dimebon on cognition, activities of daily living, behaviour, and global function in patients with mild-to-moderate Alzheimer’s disease: A randomised, double-blind, placebo-controlled study. Lancet,  2008, 372(9634), 207-215.
 [http://dx.doi.org/10.1016/S0140-6736(08)61074-0] [PMID:  18640457]

[223]
Grigor’ev, V.V.; Dranyi, O.A.; Bachurin, S.O. Comparative study of action mechanisms of dimebon and memantine on AMPA- and NMDA-subtypes glutamate receptors in rat cerebral neurons. Bull. Exp. Biol. Med.,  2003, 136(5), 474-477.
 [http://dx.doi.org/10.1023/B:BEBM.0000017097.75818.14] [PMID:  14968164]

[224]
Tang, T.S.; Slow, E.; Lupu, V.; Stavrovskaya, I.G.; Sugimori, M.; Llinás, R.; Kristal, B.S.; Hayden, M.R.; Bezprozvanny, I. Disturbed Ca2+ signaling and apoptosis of medium spiny neurons in Huntington’s disease. Proc. Natl. Acad. Sci. USA,  2005, 102(7), 2602-2607.
 [http://dx.doi.org/10.1073/pnas.0409402102] [PMID:  15695335]

[225]
Wu, J.; Li, Q.; Bezprozvanny, I. Evaluation of Dimebon in cellular model of Huntington’s disease. Mol. Neurodegener.,  2008, 3(1), 15.
 [http://dx.doi.org/10.1186/1750-1326-3-15] [PMID:  18939977]

[226]
Lermontova, N.N.; Redkozubov, A.E.; Shevtsova, E.F.; Serkova, T.P.; Kireeva, E.G.; Bachurin, S.O. Dimebon and tacrine inhibit neurotoxic action of beta-amyloid in culture and block L-type Ca2+ channels. Bull. Exp. Biol. Med.,  2001, 132(5), 1079-1083.
 [http://dx.doi.org/10.1023/A:1017972709652] [PMID:  11865327]

[227]
Bachurin, S.O.; Shevtsova, E.P.; Kireeva, E.G.; Oxenkrug, G.F.; Sablin, S.O. Mitochondria as a target for neurotoxins and neuroprotective agents. Ann. N. Y. Acad. Sci.,  2003, 993(1), 334-344.
 [http://dx.doi.org/10.1111/j.1749-6632.2003.tb07541.x] [PMID:  12853325]

[228]
Nguyen, L.; Lucke-Wold, B.P.; Mookerjee, S.A.; Cavendish, J.Z.; Robson, M.J.; Scandinaro, A.L.; Matsumoto, R.R. Role of sigma-1 receptors in neurodegenerative diseases. J. Pharmacol. Sci.,  2015, 127(1), 17-29.
 [http://dx.doi.org/10.1016/j.jphs.2014.12.005] [PMID:  25704014]

[229]
Prolla, T.A.; Mattson, M.P. Molecular mechanisms of brain aging and neurodegenerative disorders: Lessons from dietary restriction. Trends Neurosci.,  2001, 24(11), (Suppl.), S21-S31.
 [http://dx.doi.org/10.1016/S0166-2236(00)01957-3] [PMID: 11881742]

[230]
Colangelo, A.M.; Alberghina, L.; Papa, M. Astrogliosis as a therapeutic target for neurodegenerative diseases. Neurosci. Lett.,  2014, 565, 59-64.
 [http://dx.doi.org/10.1016/j.neulet.2014.01.014] [PMID:  24457173]

[231]
Kim, J.; Min, K.J.; Seol, W.; Jou, I.; Joe, E. Astrocytes in injury states rapidly produce anti-inflammatory factors and attenuate microglial inflammatory responses. J. Neurochem.,  2010, 115(5), 1161-1171.
 [http://dx.doi.org/10.1111/j.1471-4159.2010.07004.x] [PMID:  21039520]

[232]
Li, J.; Liu, D.; Sun, L.; Lu, Y.; Zhang, Z. Advanced glycation end products and neurodegenerative diseases: Mechanisms and perspective. J. Neurol. Sci.,  2012, 317(1-2), 1-5.
 [http://dx.doi.org/10.1016/j.jns.2012.02.018] [PMID:  22410257]

[233]
Dringen, R.; Gutterer, J.M.; Hirrlinger, J. Glutathione metabolism in brain. Eur. J. Biochem.,  2000, 267(16), 4912-4916.
 [http://dx.doi.org/10.1046/j.1432-1327.2000.01597.x] [PMID:  10931173]

[234]
Fernandez-Fernandez, S.; Almeida, A.; Bolaños, J.P. Antioxidant and bioenergetic coupling between neurons and astrocytes. Biochem. J.,  2012, 443(1), 3-11.
 [http://dx.doi.org/10.1042/BJ20111943] [PMID:  22417747]

[235]
Shih, A.Y.; Johnson, D.A.; Wong, G.; Kraft, A.D.; Jiang, L.; Erb, H.; Johnson, J.A.; Murphy, T.H. Coordinate regulation of glutathione biosynthesis and release by Nrf2-expressing glia potently protects neurons from oxidative stress. J. Neurosci.,  2003, 23(8), 3394-3406.
 [http://dx.doi.org/10.1523/JNEUROSCI.23-08-03394.2003] [PMID:  12716947]

[236]
Williamson, T.P.; Johnson, D.A.; Johnson, J.A. Activation of the Nrf2-ARE pathway by siRNA knockdown of Keap1 reduces oxidative stress and provides partial protection from MPTP-mediated neurotoxicity. Neurotoxicology,  2012, 33(3), 272-279.
 [http://dx.doi.org/10.1016/j.neuro.2012.01.015] [PMID:  22342405]

[237]
Reed, J.; Jurgensmeier, J.; Matsuyama, S. Bcl-2 family proteins and mitochondria. Biochim. Biophys. Acta Bioenerg.,  1998, 1366(1-2), 127-137.
 [http://dx.doi.org/10.1016/S0005-2728(98)00108-X]

[238]
Sugasawa, T.; Tome, Y.; Takeuchi, Y.; Yoshida, Y.; Yahagi, N.; Sharma, R.; Aita, Y.; Ueda, H.; Maruyama, R.; Takeuchi, K.; Morita, S.; Kawamai, Y.; Takekoshi, K. Influence of intermittent cold stimulations on CREB and its targeting genes in muscle: Investigations into molecular mechanisms of local cryotherapy. Int. J. Mol. Sci.,  2020, 21(13), 4588.
 [http://dx.doi.org/10.3390/ijms21134588] [PMID:  32605164]

[239]
Ribas, V.; García-Ruiz, C.; Fernández-Checa, J.C. Glutathione and mitochondria. Front. Pharmacol.,  2014, 5, 151.
 [http://dx.doi.org/10.3389/fphar.2014.00151] [PMID:  25024695]

[240]
Craig, E.A. Hsp70 at the membrane: Driving protein translocation. BMC Biol.,  2018, 16(1), 11.
 [http://dx.doi.org/10.1186/s12915-017-0474-3] [PMID:  29343244]

[241]
Tang, B.L. Sirt1 and the mitochondria. Mol. Cells,  2016, 39(2), 87-95.
 [http://dx.doi.org/10.14348/molcells.2016.2318] [PMID:  26831453]

[242]
Lombard, D.B.; Tishkoff, D.X.; Bao, J. Mitochondrial sirtuins in the regulation of mitochondrial activity and metabolic adaptation. Handb. Exp. Pharmacol.,  2011, 206, 163-188.
 [http://dx.doi.org/10.1007/978-3-642-21631-2_8] [PMID:  21879450]

[243]
Miriyala, S.; Holley, A.K.; St Clair, D.K. Mitochondrial superoxide dismutase-signals of distinction. Anticancer. Agents Med. Chem.,  2011, 11(2), 181-190.
 [http://dx.doi.org/10.2174/187152011795255920] [PMID:  21355846]
Cite As
Current Neuropharmacology

Mitochondrial Medicine: A Promising Therapeutic Option Against Various Neurodegenerative Disorders

Abstract

Graphical Abstract
