The multifaceted role of Nrf2 in mitochondrial function

Current Opinion in Toxicology

Volumn 2, Issue , 2016, Pages 80-91

  Holmström, Kira M ^a,b   Kostov, Rumen V ^c   Dinkova Kostova, Albena T ^c,d  

^a TAMPERE UNIVERSITY HOSPITAL   (Finland)

^b UNIVERSITY OF HELSINKI   (Finland)

^c UNIVERSITY OF DUNDEE   (United Kingdom)

^d JOHNS HOPKINS UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

Glucoraphanin; Keap1; Mitohormesis; Mitophagy; Neurodegenerative disease; Nrf; PMI; RTA 408; Stem cells; Sulforaphane

Indexed keywords

BETA SECRETASE 1; GLUTATHIONE; GLUTATHIONE REDUCTASE; REACTIVE OXYGEN METABOLITE; TRANSCRIPTION FACTOR NRF2;

ALZHEIMER DISEASE; BRAIN INJURY; CAENORHABDITIS ELEGANS; CEREBROVASCULAR ACCIDENT; CITRIC ACID CYCLE; DEPRESSION; DIET RESTRICTION; DOWNSTREAM PROCESSING; FATTY ACID OXIDATION; FRIEDREICH ATAXIA; GENE EXPRESSION; HOMEOSTASIS; HUMAN; HUNTINGTON CHOREA; MITOCHONDRIAL MEMBRANE POTENTIAL; MITOCHONDRIAL PERMEABILITY; MITOCHONDRION; MITOPHAGY; MULTIPLE SCLEROSIS; NONHUMAN; OXIDATIVE STRESS; PARKINSON DISEASE; PENTOSE PHOSPHATE CYCLE; PHASE 2 CLINICAL TRIAL (TOPIC); PRIORITY JOURNAL; PROTEIN EXPRESSION; REVIEW; SPINAL CORD INJURY;

EID: 85016784502     PISSN: None     EISSN: 24682020     Source Type: Journal    
DOI: 10.1016/j.cotox.2016.10.002     Document Type: Review

References (122)

1. 1 Holmström, K.M., Finkel, T., Cellular mechanisms and physiological consequences of redox-dependent signalling. Nat Rev Mol Cell Biol 15 (2014), 411–421.
2. 2 Nickel, A., Kohlhaas, M., Maack, C., Mitochondrial reactive oxygen species production and elimination. J Mol Cell Cardiol 73 (2014), 26–33.
3. 3 Pham-Huy, L.A., He, H., Pham-Huy, C., Free radicals, antioxidants in disease and health. Int J Biomed Sci 4 (2008), 89–96.
4. 4 Hayes, J.D., Dinkova-Kostova, A.T., The Nrf2 regulatory network provides an interface between redox and intermediary metabolism. Trends Biochem Sci 39 (2014), 199–218.
5. 5 Suzuki, T., Motohashi, H., Yamamoto, M., Toward clinical application of the Keap1–Nrf2 pathway. Trends Pharmacol Sci 34 (2013), 340–346.
6. 6 Kensler, T.W., Wakabayashi, N., Biswal, S., Cell survival responses to environmental stresses via the Keap1–Nrf2–ARE pathway. Annu Rev Pharmacol Toxicol 47 (2007), 89–116.
7. 7 Dinkova-Kostova, A.T., Abramov, A.Y., The emerging role of Nrf2 in mitochondrial function. Free Radic Biol Med 88 (2015), 179–188.
8. Dinkova-Kostova, A.T., Baird, L., Holmström, K.M., Meyer, C.J., Abramov, A.Y., The spatiotemporal regulation of the Keap1–Nrf2 pathway and its importance in cellular bioenergetics. Biochem Soc Trans 43 (2015), 602–610 Restoration of the mitochondrial membrane potential by pharmacological Nrf2 activation in PINK1-deficient primary neuronal cultures.
9. 9 Itoh, K., Ye, P., Matsumiya, T., Tanji, K., Ozaki, T., Emerging functional cross-talk between the Keap1–Nrf2 system and mitochondria. J Clin Biochem Nutr 56 (2015), 91–97.
10. 10 Esteras, N., Dinkova-Kostova, A.T., Abramov, A.Y., Nrf2 activation in the treatment of neurodegenerative diseases: a focus on its role in mitochondrial bioenergetics and function. Biol Chem 397 (2016), 383–400.
11. 11 Zhang, D.D., Lo, S.C., Cross, J.V., Templeton, D.J., Hannink, M., Keap1 is a redox-regulated substrate adaptor protein for a Cul3-dependent ubiquitin ligase complex. Mol Cell Biol 24 (2004), 10941–10953.
12. 12 Kobayashi, A., Kang, M.I., Okawa, H., Ohtsuji, M., Zenke, Y., Chiba, T., et al. Oxidative stress sensor Keap1 functions as an adaptor for Cul3-based E3 ligase to regulate proteasomal degradation of Nrf2. Mol Cell Biol 24 (2004), 7130–7139.
13. 13 Cullinan, S.B., Gordan, J.D., Jin, J., Harper, J.W., Diehl, J.A., The Keap1–BTB protein is an adaptor that bridges Nrf2 to a Cul3-based E3 ligase: oxidative stress sensing by a Cul3-Keap1 ligase. Mol Cell Biol 24 (2004), 8477–8486.
14. Itoh, K., Wakabayashi, N., Katoh, Y., Ishii, T., Igarashi, K., Engel, J.D., et al. Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain. Genes Dev 13 (1999), 76–86 Discovery of Keap1.
15. 15 Dinkova-Kostova, A.T., Holtzclaw, W.D., Cole, R.N., Itoh, K., Wakabayashi, N., Katoh, Y., et al. Direct evidence that sulfhydryl groups of Keap1 are the sensors regulating induction of phase 2 enzymes that protect against carcinogens and oxidants. Proc Natl Acad Sci U S A 99 (2002), 11908–11913.
16. 16 McMahon, M., Lamont, D.J., Beattie, K.A., Hayes, J.D., Keap1 perceives stress via three sensors for the endogenous signaling molecules nitric oxide, zinc, and alkenals. Proc Natl Acad Sci U S A 107 (2010), 18838–18843.
17. 17 Dinkova-Kostova, A.T., Liby, K.T., Stephenson, K.K., Holtzclaw, W.D., Gao, X., Suh, N., et al. Extremely potent triterpenoid inducers of the phase 2 response: correlations of protection against oxidant and inflammatory stress. Proc Natl Acad Sci U S A 102 (2005), 4584–4589.
18. 18 Dinkova-Kostova, A.T., Holtzclaw, W.D., Wakabayashi, N., Keap1, the sensor for electrophiles and oxidants that regulates the phase 2 response, is a zinc metalloprotein. Biochemistry 44 (2005), 6889–6899.
19. Baird, L., Llères, D., Swift, S., Dinkova-Kostova, A.T., Regulatory flexibility in the Nrf2-mediated stress response is conferred by conformational cycling of the Keap1–Nrf2 protein complex. Proc Natl Acad Sci U S A 110 (2013), 15259–15264 Conceptually new model of Keap1-mediated regulation of Nrf2.
20. 20 Zhang, D.D., Hannink, M., Distinct cysteine residues in Keap1 are required for Keap1-dependent ubiquitination of Nrf2 and for stabilization of Nrf2 by chemopreventive agents and oxidative stress. Mol Cell Biol 23 (2003), 8137–8151.
21. 21 Hirotsu, Y., Katsuoka, F., Funayama, R., Nagashima, T., Nishida, Y., Nakayama, K., et al. Nrf2–MafG heterodimers contribute globally to antioxidant and metabolic networks. Nucleic Acids Res 40 (2012), 10228–10239.
22. Itoh, K., Chiba, T., Takahashi, S., Ishii, T., Igarashi, K., Katoh, Y., et al. An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements. Biochem Biophys Res Commun 236 (1997), 313–322 Discovery of Nrf2 in the context of the environmantal stress response.
23. Rada, P., Rojo, A.I., Chowdhry, S., McMahon, M., Hayes, J.D., Cuadrado, A., SCF/β-TrCP promotes glycogen synthase kinase 3-dependent degradation of the Nrf2 transcription factor in a Keap1-independent manner. Mol Cell Biol 31 (2011), 1121–1133 Keap1-independent GSK3-dependend Nrf2 degradation.
24. 24 Chowdhry, S., Zhang, Y., McMahon, M., Sutherland, C., Cuadrado, A., Hayes, J.D., Nrf2 is controlled by two distinct β-TrCP recognition motifs in its Neh6 domain, one of which can be modulated by GSK-3 activity. Oncogene 32 (2013), 3765–3781.
25. Wu, T., Zhao, F., Gao, B., Tan, C., Yagishita, N., Nakajima, T., et al. Hrd1 suppresses Nrf2-mediated cellular protection during liver cirrhosis. Genes Dev 28 (2014), 708–722 Discovery of Hrd1-mediated Nrf2 degradation.
26. 26 Jain, A.K., Bloom, D.A., Jaiswal, A.K., Nuclear import and export signals in control of Nrf2. J Biol Chem 280 (2005), 29158–29168.
27. Lo, S.C., Hannink, M., PGAM5 tethers a ternary complex containing Keap1 and Nrf2 to mitochondria. Exp Cell Res 314 (2008), 1789–1803 Discovery of the Keap1–Nrf2–PGAM5 tertiary complex.
28. Plafker, K.S., Plafker, S.M., The ubiquitin-conjugating enzyme UBE2E3 and its import receptor importin-11 regulate the localization and activity of the antioxidant transcription factor NRF2. Mol Biol Cell 26 (2015), 327–338 Nrf2 regulation by endogenous UBE2E3.
29. Moi, P., Chan, K., Asunis, I., Cao, A., Kan, Y.W., Isolation of NF-E2-related factor 2 (Nrf2), a NF-E2-like basic leucine zipper transcriptional activator that binds to the tandem NF-E2/AP1 repeat of the beta-globin locus control region. Proc Natl Acad Sci U S A 91 (1994), 9926–9930 Discovery of Nrf2.
30. 30 Malhotra, D., Portales-Casamar, E., Singh, A., Srivastava, S., Arenillas, D., Happel, C., et al. Global mapping of binding sites for Nrf2 identifies novel targets in cell survival response through ChIP-Seq profiling and network analysis. Nucleic Acids Res 38 (2010), 5718–5734.
31. 31 Baird, L., Dinkova-Kostova, A.T., The cytoprotective role of the Keap1–Nrf2 pathway. Arch Toxicol 85 (2011), 241–272.
32. 32 Wild, A.C., Moinova, H.R., Mulcahy, R.T., Regulation of gamma-glutamylcysteine synthetase subunit gene expression by the transcription factor Nrf2. J Biol Chem 274 (1999), 33627–33636.
33. 33 Wild, A.C., Mulcahy, R.T., Regulation of gamma-glutamylcysteine synthetase subunit gene expression: insights into transcriptional control of antioxidant defenses. Free Radic Res 32 (2000), 281–301.
34. 34 MacLeod, A.K., McMahon, M., Plummer, S.M., Higgins, L.G., Penning, T.M., Igarashi, K., et al. Characterization of the cancer chemopreventive NRF2-dependent gene battery in human keratinocytes: demonstration that the KEAP1–NRF2 pathway, and not the BACH1–NRF2 pathway, controls cytoprotection against electrophiles as well as redox-cycling compounds. Carcinogenesis 30 (2009), 1571–1580.
35. 35 Agyeman, A.S., Chaerkady, R., Shaw, P.G., Davidson, N.E., Visvanathan, K., Pandey, A., et al. Transcriptomic and proteomic profiling of KEAP1 disrupted and sulforaphane-treated human breast epithelial cells reveals common expression profiles. Breast Cancer Res Treat 132 (2012), 175–187.
36. 36 Lee, J.M., Calkins, M.J., Chan, K., Kan, Y.W., Johnson, J.A., Identification of the NF-E2-related factor-2-dependent genes conferring protection against oxidative stress in primary cortical astrocytes using oligonucleotide microarray analysis. J Biol Chem 278 (2003), 12029–12038.
37. 37 Thimmulappa, R.K., Mai, K.H., Srisuma, S., Kensler, T.W., Yamamoto, M., Biswal, S., Identification of Nrf2-regulated genes induced by the chemopreventive agent sulforaphane by oligonucleotide microarray. Cancer Res 62 (2002), 5196–5203.
38. Mitsuishi, Y., Taguchi, K., Kawatani, Y., Shibata, T., Nukiwa, T., Aburatani, H., et al. Nrf2 redirects glucose and glutamine into anabolic pathways in metabolic reprogramming. Cancer Cell 22 (2012), 66–79 Nrf2 redirects glucose towards the pentose phosphate pathway in rapidly proliferating cells.
39. 39 Singh, A., Happel, C., Manna, S.K., Acquaah-Mensah, G., Carrerero, J., Kumar, S., et al. Transcription factor NRF2 regulates miR-1 and miR-206 to drive tumorigenesis. J Clin Invest 123 (2013), 2921–2934.
40. Wu, K.C., Cui, J.Y., Klaassen, C.D., Beneficial role of Nrf2 in regulating NADPH generation and consumption. Toxicol Sci 123 (2011), 590–600 The role of Nrf2 in NADPH generation and consumption.
41. 41 Lee, J.M., Shih, A.Y., Murphy, T.H., Johnson, J.A., NF-E2-related factor-2 mediates neuroprotection against mitochondrial complex I inhibitors and increased concentrations of intracellular calcium in primary cortical neurons. J Biol Chem 278 (2003), 37948–37956.
42. 42 Shih, A.Y., Imbeault, S., Barakauskas, V., Erb, H., Jiang, L., Li, P., et al. Induction of the Nrf2-driven antioxidant response confers neuroprotection during mitochondrial stress in vivo. J Biol Chem 280 (2005), 22925–22936.
43. Calkins, M.J., Jakel, R.J., Johnson, D.A., Chan, K., Kan, Y.W., Johnson, J.A., Protection from mitochondrial complex II inhibition in vitro and in vivo by Nrf2-mediated transcription. Proc Natl Acad Sci U S A 102 (2005), 244–249 Nrf2 protects against mitochondrial complex II inhibition.
44. 44 Matigian, N., Abrahamsen, G., Sutharsan, R., Cook, A.L., Vitale, A.M., Nouwens, A., et al. Disease-specific, neurosphere-derived cells as models for brain disorders. Dis Model Mech 3 (2010), 785–798.
45. 45 Cook, A.L., Vitale, A.M., Ravishankar, S., Matigian, N., Sutherland, G.T., Shan, J., et al. NRF2 activation restores disease related metabolic deficiencies in olfactory neurosphere-derived cells from patients with sporadic Parkinson's disease. PloS One, 6, 2011, e21907.
46. Paupe, V., Dassa, E.P., Goncalves, S., Auchere, F., Lonn, M., Holmgren, A., et al. Impaired nuclear Nrf2 translocation undermines the oxidative stress response in Friedreich ataxia. PLoS One, 4, 2009, e4253 Nrf2 signalling is impaired in Friedreich ataxia.
47. Piantadosi, C.A., Carraway, M.S., Babiker, A., Suliman, H.B., Heme oxygenase-1 regulates cardiac mitochondrial biogenesis via Nrf2-mediated transcriptional control of nuclear respiratory factor-1. Circ Res 103 (2008), 1232–1240 Nrf2 as a regulator of mitochondrial biogenesis.
48. 48 Merry, T.L., Ristow, M., Nuclear factor erythroid-derived 2-like 2 (NFE2L2, Nrf2) mediates exercise-induced mitochondrial biogenesis and antioxidant response in mice. J Physiol 594 (2016), 5195–5207.
49. Holmström, K.M., Baird, L., Zhang, Y., Hargreaves, I., Chalasani, A., Land, J.M., et al. Nrf2 impacts cellular bioenergetics by controlling substrate availability for mitochondrial respiration. Biol Open 2 (2013), 761–770 Nrf2 regulates mitochondrial function.
50. 50 Kovac, S., Angelova, P.R., Holmström, K.M., Zhang, Y., Dinkova-Kostova, A.T., Abramov, A.Y., Nrf2 regulates ROS production by mitochondria and NADPH oxidase. Biochim Biophys Acta 1850 (2014), 794–801.
51. Ludtmann, M.H., Angelova, P.R., Zhang, Y., Abramov, A.Y., Dinkova-Kostova, A.T., Nrf2 affects the efficiency of mitochondrial fatty acid oxidation. Biochem J 457 (2014), 415–424 Nrf2 affects mitochondrial fatty acid oxidation.
52. 52 Zhang, Y.K., Wu, K.C., Klaassen, C.D., Genetic activation of Nrf2 protects against fasting-induced oxidative stress in livers of mice. PLoS One, 8, 2013, e59122.
53. 53 Sun, N., Youle, R.J., Finkel, T., The mitochondrial basis of aging. Mol Cell 61 (2016), 654–666.
54. Geisler, S., Holmström, K.M., Skujat, D., Fiesel, F.C., Rothfuss, O.C., Kahle, P.J., et al. PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1. Nat Cell Biol 12 (2010), 119–131 p62 dependence of PINK1/Parkin-mediated mitophagy.
55. Komatsu, M., Kurokawa, H., Waguri, S., Taguchi, K., Kobayashi, A., Ichimura, Y., et al. The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1. Nat Cell Biol 12 (2010), 213–223 p62 activates Nrf2.
56. Jain, A., Lamark, T., Sjottem, E., Larsen, K.B., Awuh, J.A., Overvatn, A., et al. p62/SQSTM1 is a target gene for transcription factor NRF2 and creates a positive feedback loop by inducing antioxidant response element-driven gene transcription. J Biol Chem 285 (2010), 22576–22591 p62 and Nrf2 engage in a positive feedback regulatory loop.
57. Ichimura, Y., Waguri, S., Sou, Y.S., Kageyama, S., Hasegawa, J., Ishimura, R., et al. Phosphorylation of p62 activates the Keap1–Nrf2 pathway during selective autophagy. Mol Cell 51 (2013), 618–631 Phosphorylation of p62 increases its affinity to Keap1.
58. 58 Hancock, R., Bertrand, H.C., Tsujita, T., Naz, S., El-Bakry, A., Laoruchupong, J., et al. Peptide inhibitors of the Keap1–Nrf2 protein-protein interaction. Free Radic Biol Med 52 (2012), 444–451.
59. 59 Bertrand, H.C., Schaap, M., Baird, L., Georgakopoulos, N.D., Fowkes, A., Thiollier, C., et al. Design, synthesis, and evaluation of triazole derivatives that induce Nrf2 dependent gene products and inhibit the Keap1–Nrf2 protein–protein Interaction. J Med Chem 58 (2015), 7186–7194.
60. 60 East, D.A., Fagiani, F., Crosby, J., Georgakopoulos, N.D., Bertrand, H., Schaap, M., et al. PMI: a ΔΨ-independent pharmacological regulator of mitophagy. Chem Biol 21 (2014), 1585–1596.
61. 61 Izzo, V., Bravo-San Pedro, J.M., Sica, V., Kroemer, G., Galluzzi, L., Mitochondrial permeability transition: new findings and persisting uncertainties. Trends Cell Biol 26 (2016), 655–667.
62. Zhang, Y., Talalay, P., Cho, C.G., Posner, G.H., A major inducer of anticarcinogenic protective enzymes from broccoli: isolation and elucidation of structure. Proc Natl Acad Sci U S A 89 (1992), 2399–2403 Isolation of sulforaphane as the principal inducer of the prototypical Nrf2 target enzyme NQO1 from broccoli.
63. 63 Yang, L., Palliyaguru, D.L., Kensler, T.W., Frugal chemoprevention: targeting Nrf2 with foods rich in sulforaphane. Semin Oncol 43 (2016), 146–153.
64. 64 Greco, T., Fiskum, G., Brain mitochondria from rats treated with sulforaphane are resistant to redox-regulated permeability transition. J Bioenerg Biomembr 42 (2010), 491–497.
65. 65 Joshi, G., Johnson, J.A., The Nrf2–ARE pathway: a valuable therapeutic target for the treatment of neurodegenerative diseases. Recent Pat CNS Drug Discov 7 (2012), 218–229.
66. 66 Johnson, D.A., Johnson, J.A., Nrf2-a therapeutic target for the treatment of neurodegenerative diseases. Free Radic Biol Med 88 (2015), 253–267.
67. Gan, L., Vargas, M.R., Johnson, D.A., Johnson, J.A., Astrocyte-specific overexpression of Nrf2 delays motor pathology and synuclein aggregation throughout the CNS in the α-synuclein mutant (A53T) mouse model. J Neurosci 32 (2012), 17775–17787 Nrf2 overexpression in astrocytes provides neuroprotection in a mouse model of Parkinson's disease.
68. 68 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 33 (2012), 272–279.
69. Chen, P.C., Vargas, M.R., Pani, A.K., Smeyne, R.J., Johnson, D.A., Kan, Y.W., et al. Nrf2-mediated neuroprotection in the MPTP mouse model of Parkinson's disease: critical role for the astrocyte. Proc Natl Acad Sci U S A 106 (2009), 2933–2938 Astrocytic Nrf2 provides neuroprotection in a mouse model of Parkinson's disease.
70. Jazwa, A., Rojo, A.I., Innamorato, N.G., Hesse, M., Fernandez-Ruiz, J., Cuadrado, A., Pharmacological targeting of the transcription factor Nrf2 at the basal ganglia provides disease modifying therapy for experimental parkinsonism. Antioxid Redox Signal 14 (2011), 2347–2360 The Nrf2 inducer sulforaphane is neuroprotective in a mouse model of Parkinson's disease.
71. 71 Lastres-Becker, I., Ulusoy, A., Innamorato, N.G., Sahin, G., Rabano, A., Kirik, D., et al. α-Synuclein expression and Nrf2 deficiency cooperate to aggravate protein aggregation, neuronal death and inflammation in early-stage Parkinson's disease. Hum Mol Genet 21 (2012), 3173–3192.
72. Rojo, A.I., Innamorato, N.G., Martin-Moreno, A.M., De Ceballos, M.L., Yamamoto, M., Cuadrado, A., Nrf2 regulates microglial dynamics and neuroinflammation in experimental Parkinson's disease. Glia 58 (2010), 588–598 Nrf2 regulates neuroinflammation in a mouse model of Parkinson's disease.
73. 73 Abeti, R., Uzun, E., Renganathan, I., Honda, T., Pook, M.A., Giunti, P., Targeting lipid peroxidation and mitochondrial imbalance in Friedreich's ataxia. Pharmacol Res 99 (2015), 344–350.
74. 74 Kim, H.V., Kim, H.Y., Ehrlich, H.Y., Choi, S.Y., Kim, D.J., Kim, Y., Amelioration of Alzheimer's disease by neuroprotective effect of sulforaphane in animal model. Amyloid 20 (2013), 7–12.
75. 75 Tsvetkov, A.S., Arrasate, M., Barmada, S., Ando, D.M., Sharma, P., Shaby, B.A., et al. Proteostasis of polyglutamine varies among neurons and predicts neurodegeneration. Nat Chem Biol 9 (2013), 586–592.
76. Quinti, L., Casale, M., Moniot, S., Pais, T.F., Kaltenbach, L.S., Pallos, J., et al. SIRT2- and NRF2-targeting thiazole-containing compound with therapeutic activity in Huntington's disease models. Cell Chem Biol 23 (2016), 849–861 Identification of a new class of thiazole Nrf2 activators with therapeutic potential in models of Huntington's disease.
77. 77 Yang, Y., Jiang, S., Yan, J., Li, Y., Xin, Z., Lin, Y., et al. An overview of the molecular mechanisms and novel roles of Nrf2 in neurodegenerative disorders. Cytokine Growth Factor Rev 26 (2015), 47–57.
78. 78 Kawalec, P., Mikrut, A., Wisniewska, N., Pilc, A., The effectiveness of dimethyl fumarate monotherapy in the treatment of relapsing-remitting multiple sclerosis: a systematic review and meta-analysis. Curr Neuropharmacol 12 (2014), 256–268.
79. 79 Bomprezzi, R., Dimethyl fumarate in the treatment of relapsing-remitting multiple sclerosis: an overview. Ther Adv Neurol Disord 8 (2015), 20–30.
80. 80 Lovestone, S., Boada, M., Dubois, B., Hull, M., Rinne, J.O., Huppertz, H.J., et al. A phase II trial of tideglusib in Alzheimer's disease. J Alzheimers Dis 45 (2015), 75–88.
81. Singh, K., Connors, S.L., Macklin, E.A., Smith, K.D., Fahey, J.W., Talalay, P., et al. Sulforaphane treatment of autism spectrum disorder (ASD). Proc Natl Acad Sci U S A 111 (2014), 15550–15555 The Nrf2 inducer sulforaphane improves clinical outcomes in autism.
82. 82 Napoli, E., Wong, S., Hertz-Picciotto, I., Giulivi, C., Deficits in bioenergetics and impaired immune response in granulocytes from children with autism. Pediatrics 133 (2014), e1405–1410.
83. 83 Armah, C.N., Traka, M.H., Dainty, J.R., Defernez, M., Janssens, A., Leung, W., et al. A diet rich in high-glucoraphanin broccoli interacts with genotype to reduce discordance in plasma metabolite profiles by modulating mitochondrial function. Am J Clin Nutr 98 (2013), 712–722.
84. 84 Calabrese, V., Cornelius, C., Dinkova-Kostova, A.T., Iavicoli, I., Di Paola, R., Koverech, A., et al. Cellular stress responses, hormetic phytochemicals and vitagenes in aging and longevity. Biochim Biophys Acta 1822 (2012), 753–783.
85. 85 Yun, J., Finkel, T., Mitohormesis. Cell Metab 19 (2014), 757–766.
86. 86 Lindsay, D.G., Nutrition, hormetic stress and health. Nutr Res Rev 18 (2005), 249–258.
87. 87 Calabrese, V., Cornelius, C., Mancuso, C., Pennisi, G., Calafato, S., Bellia, F., et al. Cellular stress response: a novel target for chemoprevention and nutritional neuroprotection in aging, neurodegenerative disorders and longevity. Neurochem Res 33 (2008), 2444–2471.
88. 88 Hine, C.M., Mitchell, J.R., NRF2 and the phase II response in acute stress resistance induced by dietary restriction. J Clin Exp Pathol, 2012, S4.
89. 89 Steinbaugh, M.J., Narasimhan, S.D., Robida-Stubbs, S., Moronetti Mazzeo, L.E., Dreyfuss, J.M., Hourihan, J.M., et al. Lipid-mediated regulation of SKN-1/Nrf in response to germ cell absence. Elife, 2015, 4.
90. 90 Wei, Y., Kenyon, C., Roles for ROS and hydrogen sulfide in the longevity response to germline loss in Caenorhabditis elegans. Proc Natl Acad Sci U S A 113 (2016), E2832–2841.
91. 91 Ogawa, T., Kodera, Y., Hirata, D., Blackwell, T.K., Mizunuma, M., Natural thioallyl compounds increase oxidative stress resistance and lifespan in Caenorhabditis elegans by modulating SKN-1/Nrf. Sci Rep, 6, 2016, 21611.
92. Pang, S., Lynn, D.A., Lo, J.Y., Paek, J., Curran, S.P., SKN-1 and Nrf2 couples proline catabolism with lipid metabolism during nutrient deprivation. Nat Commun, 5, 2014, 5048 Nrf2 couples proline catabolism with lipid metabolism.
93. 93 Castillo-Quan, J.I., Li, L., Kinghorn, K.J., Ivanov, D.K., Tain, L.S., Slack, C., et al. Lithium promotes longevity through GSK3/NRF2-dependent hormesis. Cell Rep 15 (2016), 638–650.
94. 94 Wakabayashi, N., Itoh, K., Wakabayashi, J., Motohashi, H., Noda, S., Takahashi, S., et al. Keap1-null mutation leads to postnatal lethality due to constitutive Nrf2 activation. Nat Genet 35 (2003), 238–245.
95. 95 Tsakiri, E.N., Sykiotis, G.P., Papassideri, I.S., Terpos, E., Dimopoulos, M.A., Gorgoulis, V.G., et al. Proteasome dysfunction in Drosophila signals to an Nrf2-dependent regulatory circuit aiming to restore proteostasis and prevent premature aging. Aging Cell 12 (2013), 802–813.
96. Corenblum, M.J., Ray, S., Remley, Q.W., Long, M., Harder, B., Zhang, D.D., et al. Reduced Nrf2 expression mediates the decline in neural stem cell function during a critical middle-age period. Aging Cell 15 (2016), 725–736 Reduced Nrf2 expression mediates the decline in neural stem cell function.
97. Khacho, M., Clark, A., Svoboda, D.S., Azzi, J., MacLaurin, J.G., Meghaizel, C., et al. Mitochondrial dynamics impacts stem cell identity and fate decisions by regulating a nuclear transcriptional program. Cell Stem Cell 19 (2016), 232–247 ** Mitochondrial dynamics affects stem cell fate decisions by driving a dual program to suppress self-renewal and promote differentiation via Nrf2 signalling.
98. Hawkins, K.E., Joy, S., Delhove, J.M., Kotiadis, V.N., Fernandez, E., Fitzpatrick, L.M., et al. NRF2 orchestrates the metabolic shift during induced pluripotent stem cell reprogramming. Cell Rep 14 (2016), 1883–1891 Nrf2 orchestrates the metabolic shift during induced pluripotent stem cell reprogramming.
99. 99 Zhou, G., Meng, S., Li, Y., Ghebre, Y.T., Cooke, J.P., Optimal ROS signaling is critical for nuclear reprogramming. Cell Rep 15 (2016), 919–925.
100. Tao, G., Kahr, P.C., Morikawa, Y., Zhang, M., Rahmani, M., Heallen, T.R., et al. Pitx2 promotes heart repair by activating the antioxidant response after cardiac injury. Nature 534 (2016), 119–123 Nrf2 signalling is critical for heart repair.
101. Kubben, N., Zhang, W., Wang, L., Voss, T.C., Yang, J., Qu, J., et al. Repression of the antioxidant Nrf2 pathway in premature aging. Cell 165 (2016), 1361–1374 Nrf2 signalling is repressed in premature aging.
102. 102 Gabriel, D., Roedl, D., Gordon, L.B., Djabali, K., Sulforaphane enhances progerin clearance in Hutchinson-Gilford progeria fibroblasts. Aging Cell 14 (2015), 78–91.
103. 103 Sazanov, L.A., A giant molecular proton pump: structure and mechanism of respiratory complex I. Nat Rev Mol Cell Biol 16 (2015), 375–388.
104. 104 Zhao, J., Moore, A.N., Clifton, G.L., Dash, P.K., Sulforaphane enhances aquaporin-4 expression and decreases cerebral edema following traumatic brain injury. J Neurosci Res 82 (2005), 499–506.
105. 105 Zhao, J., Moore, A.N., Redell, J.B., Dash, P.K., Enhancing expression of Nrf2-driven genes protects the blood brain barrier after brain injury. J Neurosci 27 (2007), 10240–10248.
106. 106 Hong, Y., Yan, W., Chen, S., Sun, C.R., Zhang, J.M., The role of Nrf2 signaling in the regulation of antioxidants and detoxifying enzymes after traumatic brain injury in rats and mice. Acta Pharmacol Sin 31 (2010), 1421–1430.
107. 107 Chen, G., Fang, Q., Zhang, J., Zhou, D., Wang, Z., Role of the Nrf2–ARE pathway in early brain injury after experimental subarachnoid hemorrhage. J Neurosci Res 89 (2011), 515–523.
108. 108 Mao, L., Wang, H.D., Wang, X.L., Qiao, L., Yin, H.X., Sulforaphane attenuates matrix metalloproteinase-9 expression following spinal cord injury in mice. Ann Clin Lab Sci 40 (2010), 354–360.
109. 109 Mao, L., Wang, H., Wang, X., Liao, H., Zhao, X., Transcription factor Nrf2 protects the spinal cord from inflammation produced by spinal cord injury. J Surg Res 170 (2011), e105–115.
110. 110 Wang, X., de Rivero Vaccari, J.P., Wang, H., Diaz, P., German, R., Marcillo, A.E., et al. Activation of the nuclear factor e2-related factor 2/antioxidant response element pathway is neuroprotective after spinal cord injury. J Neurotrauma 29 (2012), 936–945.
111. 111 Benedict, A.L., Mountney, A., Hurtado, A., Bryan, K.E., Schnaar, R.L., Dinkova-Kostova, A.T., et al. Neuroprotective effects of sulforaphane after contusive spinal cord injury. J Neurotrauma 29 (2012), 2576–2586.
112. 112 Zhao, J., Kobori, N., Aronowski, J., Dash, P.K., Sulforaphane reduces infarct volume following focal cerebral ischemia in rodents. Neurosci Lett 393 (2006), 108–112.
113. 113 Innamorato, N.G., Jazwa, A., Rojo, A.I., Garcia, C., Fernandez-Ruiz, J., Grochot-Przeczek, A., et al. Different susceptibility to the Parkinson's toxin MPTP in mice lacking the redox master regulator Nrf2 or its target gene heme oxygenase-1. PLoS One, 5, 2010, e11838.
114. 114 Morroni, F., Tarozzi, A., Sita, G., Bolondi, C., Zolezzi Moraga, J.M., Cantelli-Forti, G., et al. Neuroprotective effect of sulforaphane in 6-hydroxydopamine-lesioned mouse model of Parkinson's disease. Neurotoxicology 36 (2013), 63–71.
115. 115 Zhou, Q., Chen, B., Wang, X., Wu, L., Yang, Y., Cheng, X., et al. Sulforaphane protects against rotenone-induced neurotoxicity in vivo: involvement of the mTOR, Nrf2, and autophagy pathways. Sci Rep, 6, 2016, 32206.
116. 116 Santana-Martinez, R.A., Galvan-Arzate, S., Hernandez-Pando, R., Chanez-Cardenas, M.E., Avila-Chavez, E., Lopez-Acosta, G., et al. Sulforaphane reduces the alterations induced by quinolinic acid: modulation of glutathione levels. Neuroscience 272 (2014), 188–198.
117. 117 Luis-Garcia ER, Limon-Pacheco JH, Serrano-Garcia N, Hernandez-Perez AD, Pedraza-Chaverri J, Orozco-Ibarra M: Sulforaphane prevents quinolinic acid-induced mitochondrial dysfunction in rat striatum. J Biochem Mol Toxicol 2016; (in press).
118. 118 Martin-de-Saavedra, M.D., Budni, J., Cunha, M.P., Gomez-Rangel, V., Lorrio, S., Del Barrio, L., et al. Nrf2 participates in depressive disorders through an anti-inflammatory mechanism. Psychoneuroendocrinology 38 (2013), 2010–2022.
119. 119 Wu, S., Gao, Q., Zhao, P., Gao, Y., Xi, Y., Wang, X., et al. Sulforaphane produces antidepressant- and anxiolytic-like effects in adult mice. Behav Brain Res 301 (2016), 55–62.
120. 120 Yao, W., Zhang, J.C., Ishima, T., Dong, C., Yang, C., Ren, Q., et al. Role of Keap1–Nrf2 signaling in depression and dietary intake of glucoraphanin confers stress resilience in mice. Sci Rep, 6, 2016, 30659.
121. 121 Li, B., Cui, W., Liu, J., Li, R., Liu, Q., Xie, X.H., et al. Sulforaphane ameliorates the development of experimental autoimmune encephalomyelitis by antagonizing oxidative stress and Th17-related inflammation in mice. Exp Neurol 250 (2013), 239–249.
122. 122 Giacoppo, S., Galuppo, M., Iori, R., De Nicola, G.R., Cassata, G., Bramanti, P., et al. Protective role of (RS)-glucoraphanin bioactivated with myrosinase in an experimental model of multiple sclerosis. CNS Neurosci Ther 19 (2013), 577–584.