Advertisement

Emerging evidence for crosstalk between Nrf2 and mitochondria in physiological homeostasis and in heart disease

  • Michiko Tsushima
  • Jun Liu
  • Wataru Hirao
  • Hiromi Yamazaki
  • Hirofumi Tomita
  • Ken ItohEmail author
Review

Abstract

Nrf2 regulates redox homeostasis in cells by coordinately regulating a range of antioxidant enzymes and proteins. An increase in oxidative stress is one of the hallmarks of aging, and Nrf2 protein levels and activity decrease with aging. Decreased mitochondrial functions, such as decreased ATP production, also occur with aging, leading to the increased generation of reactive oxygen species (ROS) and oxidative stress. Thus, understanding the relationships between Nrf2 and the mitochondria is important for clarifying the regulatory mechanisms of aging. It is becoming clear that Nrf2 is activated in a tissue-specific manner in response to mitochondrial or NADPH oxidase-generated ROS. As the heart consists of postmitotic cells that utilize ATP produced mainly by mitochondrial oxidative phosphorylation, cardiomyocytes are equipped with highly sophisticated mitochondrial quality control mechanisms. Consistent with these findings, it has been reported that Nrf2 in the heart is regulated via a specific translational mechanism and that Nrf2 activation confers cardioprotective effects in various disease models. Thus, Nrf2 is a promising target for anti-aging strategies to combat age-related heart diseases, such as age-related cardiomyopathy.

Keywords

Nrf2 Mitocondria Reactive oxygen species Mitohormesis Heart 

Notes

Acknowledgements

We thank Drs. Junsei Mimura and Shuya Kasai for the critical reading and suggestions for the manuscript. This work was supported by MEXT/JSPS KAKENHI Grant No. (26111010) and a Hirosaki University Institutional Research Grant.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interest.

References

  1. Ago T, Kuroda J, Pain J, Fu C, Li H, Sadoshima J (2010) Upregulation of Nox4 by hypertrophic stimuli promotes apoptosis and mitochondrial dysfunction in cardiac myocytes. Circ Res 106:1253–1264PubMedPubMedCentralCrossRefGoogle Scholar
  2. Al-Mehdi AB, Pastukh VM, Swiger BM, Reed DJ, Patel MR, Bardwell GC, Pastukh VV, Alexeyev MF, Gillespie MN (2012) Perinuclear mitochondrial clustering creates an oxidant-rich nuclear domain required for hypoxia-induced transcription. Sci Signal 5:ra47PubMedPubMedCentralCrossRefGoogle Scholar
  3. Ashrafian H, Czibik G, Bellahcene M, Aksentijevic D, Smith AC, Mitchell SJ, Dodd MS, Kirwan J, Byrne JJ, Ludwig C, Isackson H, Yavari A, Stottrup NB, Contractor H, Cahill TJ, Sahgal N, Ball DR, Birkler RI, Hargreaves I, Tennant DA, Land J, Lygate CA, Johannsen M, Kharbanda RK, Neubauer S, Redwood C, de Cabo R, Ahmet I, Talan M, Gunther UL, Robinson AJ, Viant MR, Pollard PJ, Tyler DJ, Watkins H (2012) Fumarate is cardioprotective via activation of the Nrf2 antioxidant pathway. Cell Metab 15:361–371PubMedPubMedCentralCrossRefGoogle Scholar
  4. Bauer NG, Richter-Landsberg C (2006) The dynamic instability of microtubules is required for aggresome formation in oligodendroglial cells after proteolytic stress. J Mol Neurosci 29:153–168PubMedCrossRefGoogle Scholar
  5. Blackwell TK, Steinbaugh MJ, Hourihan JM, Ewald CY, Isik M (2015) SKN-1/Nrf, stress responses, and aging in Caenorhabditis elegans. Free Radic Biol Med 88:290–301PubMedPubMedCentralCrossRefGoogle Scholar
  6. Block K, Gorin Y, Abboud HE (2009) Subcellular localization of Nox4 and regulation in diabetes. Proc Natl Acad Sci USA 106:14385–14390PubMedCrossRefGoogle Scholar
  7. Cai Q, Zakaria HM, Simone A, Sheng ZH (2012) Spatial parkin translocation and degradation of damaged mitochondria via mitophagy in live cortical neurons. Curr Biol 22:545–552PubMedPubMedCentralCrossRefGoogle Scholar
  8. Charni S, de Bettignies G, Rathore MG, Aguilo JI, van den Elsen PJ, Haouzi D, Hipskind RA, Enriquez JA, Sanchez-Beato M, Pardo J, Anel A, Villalba M (2010) Oxidative phosphorylation induces de novo expression of the MHC class I in tumor cells through the ERK5 pathway. J Immunol 185:3498–3503PubMedCrossRefGoogle Scholar
  9. Chien WL, Lee TR, Hung SY, Kang KH, Lee MJ, Fu WM (2011) Impairment of oxidative stress-induced heme oxygenase-1 expression by the defect of Parkinson-related gene of PINK1. J Neurochem 117:643–653PubMedGoogle Scholar
  10. Cox CS, McKay SE, Holmbeck MA, Christian BE, Scortea AC, Tsay AJ, Newman LE, Shadel GS (2018) Mitohormesis in mice via sustained basal activation of mitochondrial and antioxidant signaling. Cell Metab 28(776–786):e775Google Scholar
  11. Falcon P, Escandon M, Brito A, Matus S (2019) Nutrient sensing and redox balance: GCN2 as a new integrator in aging. Oxid Med Cell Longev 2019:5730532PubMedPubMedCentralCrossRefGoogle Scholar
  12. Fiorani M, Guidarelli A, Capellacci V, Cerioni L, Crinelli R, Cantoni O (2018) The dual role of mitochondrial superoxide in arsenite toxicity: signaling at the boundary between apoptotic commitment and cytoprotection. Toxicol Appl Pharmacol 345:26–35PubMedCrossRefGoogle Scholar
  13. Fujii S, Sawa T, Ihara H, Tong KI, Ida T, Okamoto T, Ahtesham AK, Ishima Y, Motohashi H, Yamamoto M, Akaike T (2010) The critical role of nitric oxide signaling, via protein S-guanylation and nitrated cyclic GMP, in the antioxidant adaptive response. J Biol Chem 285:23970–23984PubMedPubMedCentralCrossRefGoogle Scholar
  14. Fujita Y, Taniguchi Y, Shinkai S, Tanaka M, Ito M (2016) Secreted growth differentiation factor 15 as a potential biomarker for mitochondrial dysfunctions in aging and age-related disorders. Geriatr Gerontol Int 16(Suppl 1):17–29PubMedCrossRefGoogle Scholar
  15. Gacesa R, Dunlap WC, Barlow DJ, Laskowski RA, Long PF (2016) Rising levels of atmospheric oxygen and evolution of Nrf2. Sci Rep 6:27740PubMedPubMedCentralCrossRefGoogle Scholar
  16. Geng J, Sun X, Wang P, Zhang S, Wang X, Wu H, Hong L, Xie C, Li X, Zhao H, Liu Q, Jiang M, Chen Q, Zhang J, Li Y, Song S, Wang HR, Zhou R, Johnson RL, Chien KY, Lin SC, Han J, Avruch J, Chen L, Zhou D (2015) Kinases Mst1 and Mst2 positively regulate phagocytic induction of reactive oxygen species and bactericidal activity. Nat Immunol 16:1142–1152PubMedPubMedCentralCrossRefGoogle Scholar
  17. Green DR, Galluzzi L, Kroemer G (2011) Mitochondria and the autophagy-inflammation-cell death axis in organismal aging. Science 333:1109–1112PubMedPubMedCentralCrossRefGoogle Scholar
  18. Hallmann A, Milczarek R, Lipinski M, Kossowska E, Spodnik JH, Wozniak M, Wakabayashi T, Klimek J (2004) Fast perinuclear clustering of mitochondria in oxidatively stressed human choriocarcinoma cells. Folia Mrophol 63:407–412Google Scholar
  19. Hancock M, Hafstad AD, Nabeebaccus AA, Catibog N, Logan A, Smyrnias I, Hansen SS, Lanner J, Schroder K, Murphy MP, Shah AM, Zhang M (2018) Myocardial NADPH oxidase-4 regulates the physiological response to acute exercise. eLife 7:e41044PubMedPubMedCentralCrossRefGoogle Scholar
  20. Hare JM, Stamler JS (2005) NO/redox disequilibrium in the failing heart and cardiovascular system. J Clin Invest 115:509–517PubMedPubMedCentralCrossRefGoogle Scholar
  21. Hashizume O, Ohnishi S, Mito T, Shimizu A, Ishikawa K, Nakada K, Soda M, Mano H, Togayachi S, Miyoshi H, Okita K, Hayashi J (2015) Epigenetic regulation of the nuclear-coded GCAT and SHMT2 genes confers human age-associated mitochondrial respiration defects. Sci Rep 5:10434PubMedPubMedCentralCrossRefGoogle Scholar
  22. Held NM, Houtkooper RH (2015) Mitochondrial quality control pathways as determinants of metabolic health. BioEssays 37:867–876PubMedPubMedCentralCrossRefGoogle Scholar
  23. Hosoya T, Maruyama A, Kang MI, Kawatani Y, Shibata T, Uchida K, Warabi E, Noguchi N, Itoh K, Yamamoto M (2005) Differential responses of the Nrf2-Keap1 system to laminar and oscillatory shear stresses in endothelial cells. J Biol Chem 280:27244–27250PubMedCrossRefGoogle Scholar
  24. Hu H, Tian M, Ding C, Yu S (2019) The c/ebp homologous protein (chop) transcription factor functions in endoplasmic reticulum stress-induced apoptosis and microbial infection. Front Immunol 9Google Scholar
  25. Huang ML, Sivagurunathan S, Ting S, Jansson PJ, Austin CJ, Kelly M, Semsarian C, Zhang D, Richardson DR (2013) Molecular and functional alterations in a mouse cardiac model of Friedreich ataxia: activation of the integrated stress response, eIF2alpha phosphorylation, and the induction of downstream targets. Am J Pathol 183:745–757PubMedCrossRefGoogle Scholar
  26. Hull TD, Boddu R, Guo L, Tisher CC, Traylor AM, Patel B, Joseph R, Prabhu SD, Suliman HB, Piantadosi CA, Agarwal A, George JF (2016) Heme oxygenase-1 regulates mitochondrial quality control in the heart. JCI Insight 1:e85817PubMedPubMedCentralCrossRefGoogle Scholar
  27. Indo HP, Hawkins CL, Nakanishi I, Matsumoto KI, Matsui H, Suenaga S, Davies MJ, St Clair DK, Ozawa T, Majima HJ (2017) Role of mitochondrial reactive oxygen species in the activation of cellular signals, molecules, and function. Handb Exp Pharmacol 240:439–456PubMedCrossRefGoogle Scholar
  28. Ishii T, Itoh K, Takahashi S, Sato H, Yanagawa T, Katoh Y, Bannai S, Yamamoto M (2000) Transcription factor Nrf2 coordinately regulates a group of oxidative stress-inducible genes in macrophages. J Biol Chem 275:16023–16029PubMedCrossRefGoogle Scholar
  29. Itoh K, Chiba T, Takahashi S, Ishii T, Igarashi K, Katoh Y, Oyake T, Hayashi N, Satoh K, Hatayama I, Yamamoto M, Nabeshima Y (1997) An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements. Biochem Biophys Res Commun 236:313–322PubMedCrossRefGoogle Scholar
  30. Itoh K, Mochizuki M, Ishii Y, Ishii T, Shibata T, Kawamoto Y, Kelly V, Sekizawa K, Uchida K, Yamamoto M (2004) Transcription factor Nrf2 regulates inflammation by mediating the effect of 15-deoxy-∆12,14-prostaglandin J2. Mol Cell Biol 24:36–45PubMedPubMedCentralCrossRefGoogle Scholar
  31. Itoh K, Mimura J, Yamamoto M (2010) Discovery of the negative regulator of Nrf2, Keap1: a historical overview. Antioxid Redox Signal 13:1665–1678PubMedCrossRefGoogle Scholar
  32. Itoh K, Ye P, Matsumiya T, Tanji K, Ozaki T (2015) Emerging functional cross-talk between the Keap1-Nrf2 system and mitochondria. J Clin Biochem Nutr 56:91–97PubMedPubMedCentralCrossRefGoogle Scholar
  33. Jonsson WO, Margolies NS, Anthony TG (2019) Dietary sulfur amino acid restriction and the integrated stress response: mechanistic insights. Nutrients 11:1349PubMedCentralCrossRefPubMedGoogle Scholar
  34. Kasai S, Yamazaki H, Tanji K, Engler MJ, Matsumiya T, Itoh K (2019) Role of the ISR-ATF4 pathway and its cross talk with Nrf2 in mitochondrial quality control. J Clin Biochem Nutr 64:1–12PubMedCrossRefGoogle Scholar
  35. Khan AUH, Rathore MG, Allende-Vega N, Vo DN, Belkhala S, Orecchioni S, Talarico G, Bertolini F, Cartron G, Lecellier CH, Villalba M (2016) Human leukemic cells performing oxidative phosphorylation (OXPHOS) generate an antioxidant response independently of reactive oxygen species (ROS) production. EBioMedicine 3:43–53PubMedCrossRefGoogle Scholar
  36. Khan AUH, Allende-Vega N, Gitenay D, Garaude J, Vo DN, Belkhala S, Gerbal-Chaloin S, Gondeau C, Daujat-Chavanieu M, Delettre C, Orecchioni S, Talarico G, Bertolini F, Anel A, Cuezva JM, Enriquez JA, Cartron G, Lecellier CH, Hernandez J, Villalba M (2018) Mitochondrial Complex I activity signals antioxidant response through ERK5. Sci Rep 8:7420PubMedPubMedCentralCrossRefGoogle Scholar
  37. Kim M, Kim S, Lim JH, Lee C, Choi HC, Woo CH (2012) Laminar flow activation of ERK5 protein in vascular endothelium leads to atheroprotective effect via NF-E2-related factor 2 (Nrf2) activation. J Biol Chem 287:40722–40731PubMedPubMedCentralCrossRefGoogle Scholar
  38. Kubben N, Zhang W, Wang L, Voss TC, Yang J, Qu J, Liu GH, Misteli T (2016) Repression of the antioxidant NRF2 pathway in premature aging. Cell 165:1361–1374PubMedPubMedCentralCrossRefGoogle Scholar
  39. Le NT, Heo KS, Takei Y, Lee H, Woo CH, Chang E, McClain C, Hurley C, Wang X, Li F, Xu H, Morrell C, Sullivan MA, Cohen MS, Serafimova IM, Taunton J, Fujiwara K, Abe J (2013) A crucial role for p90RSK-mediated reduction of ERK5 transcriptional activity in endothelial dysfunction and atherosclerosis. Circulation 127:486–499PubMedCrossRefGoogle Scholar
  40. Lee SC, Zhang J, Strom J, Yang D, Dinh TN, Kappeler K, Chen QM (2017) G-quadruplex in the NRF2 mRNA 5′ untranslated region regulates de novo NRF2 protein translation under oxidative stress. Mol Cell Biol 37:e00122PubMedPubMedCentralGoogle Scholar
  41. Lewis KN, Wason E, Edrey YH, Kristan DM, Nevo E, Buffenstein R (2015) Regulation of Nrf2 signaling and longevity in naturally long-lived rodents. Proc Natl Acad Sci USA 112:3722–3727PubMedGoogle Scholar
  42. Liu W, Ruiz-Velasco A, Wang S, Khan S, Zi M, Jungmann A, Dolores Camacho-Munoz M, Guo J, Du G, Xie L, Oceandy D, Nicolaou A, Galli G, Muller OJ, Cartwright EJ, Ji Y, Wang X (2017) Metabolic stress-induced cardiomyopathy is caused by mitochondrial dysfunction due to attenuated Erk5 signaling. Nat Commun 8:494PubMedPubMedCentralCrossRefGoogle Scholar
  43. Lo SC, Hannink M (2008) PGAM5 tethers a ternary complex containing Keap1 and Nrf2 to mitochondria. Exp Cell Res 314:1789–1803PubMedPubMedCentralCrossRefGoogle Scholar
  44. Lopez-Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G (2013) The hallmarks of aging. Cell 153:1194–1217PubMedPubMedCentralCrossRefGoogle Scholar
  45. Mills EL, Ryan DG, Prag HA, Dikovskaya D, Menon D, Zaslona Z, Jedrychowski MP, Costa ASH, Higgins M, Hams E, Szpyt J, Runtsch MC, King MS, McGouran JF, Fischer R, Kessler BM, McGettrick AF, Hughes MM, Carroll RG, Booty LM, Knatko EV, Meakin PJ, Ashford MLJ, Modis LK, Brunori G, Sevin DC, Fallon PG, Caldwell ST, Kunji ERS, Chouchani ET, Frezza C, Dinkova-Kostova AT, Hartley RC, Murphy MP, O’Neill LA (2018) Itaconate is an anti-inflammatory metabolite that activates Nrf2 via alkylation of KEAP1. Nature 556:113–117PubMedPubMedCentralCrossRefGoogle Scholar
  46. Mimura J, Inose-Maruyama A, Taniuchi S, Kosaka K, Yoshida H, Yamazaki H, Kasai S, Harada N, Kaufman RJ, Oyadomari S, Itoh K (2019) Concomitant Nrf2- and ATF4-activation by carnosic acid cooperatively induces expression of cytoprotective genes. Int J Mol Sci 20:1706PubMedCentralCrossRefPubMedGoogle Scholar
  47. Morais VA, Haddad D, Craessaerts K, De Bock PJ, Swerts J, Vilain S, Aerts L, Overbergh L, Grunewald A, Seibler P, Klein C, Gevaert K, Verstreken P, De Strooper B (2014) PINK1 loss-of-function mutations affect mitochondrial complex I activity via NdufA10 ubiquinone uncoupling. Science 344:203–207PubMedCrossRefGoogle Scholar
  48. Murata H, Takamatsu H, Liu S, Kataoka K, Huh NH, Sakaguchi M (2015) NRF2 regulates PINK1 expression under oxidative stress conditions. PLoS ONE 10:e0142438PubMedPubMedCentralCrossRefGoogle Scholar
  49. Muthusamy VR, Kannan S, Sadhaasivam K, Gounder SS, Davidson CJ, Boeheme C, Hoidal JR, Wang L, Rajasekaran NS (2012) Acute exercise stress activates Nrf2/ARE signaling and promotes antioxidant mechanisms in the myocardium. Free Radic Biol Med 52:366–376PubMedCrossRefGoogle Scholar
  50. Nagar S, Noveral SM, Trudler D, Lopez KM, McKercher SR, Han X, Yates JR 3rd, Pina-Crespo JC, Nakanishi N, Satoh T, Okamoto SI, Lipton SA (2017) MEF2D haploinsufficiency downregulates the NRF2 pathway and renders photoreceptors susceptible to light-induced oxidative stress. Proc Natl Acad Sci USA 114:E4048–e4056PubMedCrossRefGoogle Scholar
  51. Nakayama H, Otsu K (2018) Mitochondrial DNA as an inflammatory mediator in cardiovascular diseases. Biochem J 475:839–852PubMedPubMedCentralCrossRefGoogle Scholar
  52. Okatsu K, Saisho K, Shimanuki M, Nakada K, Shitara H, Sou YS, Kimura M, Sato S, Hattori N, Komatsu M, Tanaka K, Matsuda N (2010) p62/SQSTM1 cooperates with Parkin for perinuclear clustering of depolarized mitochondria. Genes Cells 15:887–900PubMedPubMedCentralGoogle Scholar
  53. O’Mealey GB, Plafker KS, Berry WL, Janknecht R, Chan JY, Plafker SM (2017) A PGAM5-KEAP1-Nrf2 complex is required for stress-induced mitochondrial retrograde trafficking. J Cell Sci 130:3467–3480PubMedPubMedCentralCrossRefGoogle Scholar
  54. Pajares M, Jimenez-Moreno N, Garcia-Yague AJ, Escoll M, de Ceballos ML, Van Leuven F, Rabano A, Yamamoto M, Rojo AI, Cuadrado A (2016) Transcription factor NFE2L2/NRF2 is a regulator of macroautophagy genes. Autophagy 12:1902–1916PubMedPubMedCentralCrossRefGoogle Scholar
  55. Piantadosi CA, Carraway MS, Babiker A, Suliman HB (2008) Heme oxygenase-1 regulates cardiac mitochondrial biogenesis via Nrf2-mediated transcriptional control of nuclear respiratory factor-1. Circ Res 103:1232–1240PubMedPubMedCentralCrossRefGoogle Scholar
  56. Pulliam DA, Deepa SS, Liu Y, Hill S, Lin AL, Bhattacharya A, Shi Y, Sloane L, Viscomi C, Zeviani M, Van Remmen H (2014) Complex IV-deficient Surf1(-/-) mice initiate mitochondrial stress responses. Biochem J 462:359–371PubMedPubMedCentralCrossRefGoogle Scholar
  57. Radhakrishnan SK, Lee CS, Young P, Beskow A, Chan JY, Deshaies RJ (2010) Transcription factor Nrf1 mediates the proteasome recovery pathway after proteasome inhibition in mammalian cells. Mol Cell 38:17–28PubMedPubMedCentralCrossRefGoogle Scholar
  58. Rashid AJ, Cole CJ, Josselyn SA (2014) Emerging roles for MEF2 transcription factors in memory. Genes Brain Behav 13:118–125PubMedCrossRefGoogle Scholar
  59. Ricart KC, Bolisetty S, Johnson MS, Perez J, Agarwal A, Murphy MP, Landar A (2009) The permissive role of mitochondria in the induction of haem oxygenase-1 in endothelial cells. Biochem J 419:427–436PubMedPubMedCentralCrossRefGoogle Scholar
  60. Ristow M, Zarse K, Oberbach A, Kloting N, Birringer M, Kiehntopf M, Stumvoll M, Kahn CR, Bluher M (2009) Antioxidants prevent health-promoting effects of physical exercise in humans. Proc Natl Acad Sci USA 106:8665–8670PubMedCrossRefGoogle Scholar
  61. Sahin E, Colla S, Liesa M, Moslehi J, Muller FL, Guo M, Cooper M, Kotton D, Fabian AJ, Walkey C, Maser RS, Tonon G, Foerster F, Xiong R, Wang YA, Shukla SA, Jaskelioff M, Martin ES, Heffernan TP, Protopopov A, Ivanova E, Mahoney JE, Kost-Alimova M, Perry SR, Bronson R, Liao R, Mulligan R, Shirihai OS, Chin L, DePinho RA (2011) Telomere dysfunction induces metabolic and mitochondrial compromise. Nature 470:359–365PubMedPubMedCentralCrossRefGoogle Scholar
  62. Santos CX, Hafstad AD, Beretta M, Zhang M, Molenaar C, Kopec J, Fotinou D, Murray TV, Cobb AM, Martin D, Zeh Silva M, Anilkumar N, Schroder K, Shanahan CM, Brewer AC, Brandes RP, Blanc E, Parsons M, Belousov V, Cammack R, Hider RC, Steiner RA, Shah AM (2016) Targeted redox inhibition of protein phosphatase 1 by Nox4 regulates eIF2alpha-mediated stress signaling. EMBO J 35:319–334PubMedPubMedCentralCrossRefGoogle Scholar
  63. Schmidlin CJ, Dodson MB, Madhavan L, Zhang DD (2019) Redox regulation by NRF2 in aging and disease. Free Radic Biol Med 134:702–707PubMedCrossRefGoogle Scholar
  64. Suh JH, Shenvi SV, Dixon BM, Liu H, Jaiswal AK, Liu RM, Hagen TM (2004) Decline in transcriptional activity of Nrf2 causes age-related loss of glutathione synthesis, which is reversible with lipoic acid. Proc Nat Acad Sci 101(10):3381–3386CrossRefGoogle Scholar
  65. Smyrnias I, Zhang X, Zhang M, Murray TV, Brandes RP, Schroder K, Brewer AC, Shah AM (2015) Nicotinamide adenine dinucleotide phosphate oxidase-4-dependent upregulation of nuclear factor erythroid-derived 2-like 2 protects the heart during chronic pressure overload. Hypertension 65:547–553PubMedCrossRefGoogle Scholar
  66. Strom J, Xu B, Tian X, Chen QM (2016) Nrf2 protects mitochondrial decay by oxidative stress. FASEB J 30:66–80PubMedCrossRefGoogle Scholar
  67. Suzuki T, Muramatsu A, Saito R, Iso T, Shibata T, Kuwata K, Kawaguchi SI, Iwawaki T, Adachi S, Suda H, Morita M, Uchida K, Baird L, Yamamoto M (2019) Molecular mechanism of cellular oxidative stress sensing by Keap1. Cell Rep 28(746–758):e744Google Scholar
  68. Takeya R, Ueno N, Sumimoto H (2006) Regulation of superoxide-producing NADPH oxidases in nonphagocytic cells. Methods Enzymol 406:456–468PubMedCrossRefGoogle Scholar
  69. Tomlin FM, Gerling-Driessen UIM, Liu YC, Flynn RA, Vangala JR, Lentz CS, Clauder-Muenster S, Jakob P, Mueller WF, Ordonez-Rueda D, Paulsen M, Matsui N, Foley D, Rafalko A, Suzuki T, Bogyo M, Steinmetz LM, Radhakrishnan SK, Bertozzi CR (2017) Inhibition of NGLY1 inactivates the transcription factor Nrf1 and potentiates proteasome inhibitor cytotoxicity. ACS Cent Sci 3:1143–1155PubMedPubMedCentralCrossRefGoogle Scholar
  70. Trewin AJ, Bahr LL, Almast A, Berry BJ, Wei AY, Foster TH, Wojtovich AP (2019) Mitochondrial ROS generated at the complex-II matrix or intermembrane space microdomain have distinct effects on redox signaling and stress sensitivity in C. elegans. Antioxid Redox Signal 20:594–607CrossRefGoogle Scholar
  71. Vu HT, Kotla S, Ko KA, Fujii Y, Tao Y, Medina J, Thomas T, Hada M, Sood AK, Singh PK, Milgrom SA, Krishnan S, Fujiwara K, Le NT, Abe JI (2018) Ionizing radiation induces endothelial inflammation and apoptosis via p90RSK-mediated ERK5 S496 phosphorylation. Front Cardiovasc Med 5:23PubMedPubMedCentralCrossRefGoogle Scholar
  72. Wanders D, Stone KP, Forney LA, Cortez CC, Dille KN, Simon J, Xu M, Hotard EC, Nikonorova IA, Pettit AP, Anthony TG, Gettys TW (2016) Role of GCN2-independent signaling through a noncanonical PERK/NRF2 pathway in the physiological responses to dietary methionine restriction. Diabetes 65:1499–1510PubMedPubMedCentralCrossRefGoogle Scholar
  73. Wang J, Konishi T (2019) Nuclear factor (erythroid-derived 2)-like 2 antioxidative response mitigates cytoplasmic radiation-induced DNA double-strand breaks. Cancer Sci 110:686–696PubMedPubMedCentralCrossRefGoogle Scholar
  74. Wang Y, Lei T, Yuan J, Wu Y, Shen X, Gao J, Feng W, Lu Z (2018) GCN2 deficiency ameliorates doxorubicin-induced cardiotoxicity by decreasing cardiomyocyte apoptosis and myocardial oxidative stress. Redox Biol 17:25–34PubMedPubMedCentralCrossRefGoogle Scholar
  75. Wang P, Geng J, Gao J, Zhao H, Li J, Shi Y, Yang B, Xiao C, Linghu Y, Sun X, Chen X, Hong L, Qin F, Li X, Yu JS, You H, Yuan Z, Zhou D, Johnson RL, Chen L (2019) Macrophage achieves self-protection against oxidative stress-induced ageing through the Mst-Nrf2 axis. Nat Commun 10:755PubMedPubMedCentralCrossRefGoogle Scholar
  76. Wen JJ, Porter C, Garg NJ (2017) Inhibition of NFE2L2-antioxidant response element pathway by mitochondrial reactive oxygen species contributes to development of cardiomyopathy and left ventricular dysfunction in Chagas disease. Antioxid Redox Signal 27:550–566PubMedPubMedCentralCrossRefGoogle Scholar
  77. Wu Z, Sawada T, Shiba K, Liu S, Kanao T, Takahashi R, Hattori N, Imai Y, Lu B (2013) Tricornered/NDR kinase signaling mediates PINK1-directed mitochondrial quality control and tissue maintenance. Genes Dev 27:157–162PubMedPubMedCentralCrossRefGoogle Scholar
  78. Xiao L, Xu X, Zhang F, Wang M, Xu Y, Tang D, Wang J, Qin Y, Liu Y, Tang C, He L, Greka A, Zhou Z, Liu F, Dong Z, Sun L (2017) The mitochondria-targeted antioxidant MitoQ ameliorated tubular injury mediated by mitophagy in diabetic kidney disease via Nrf2/PINK1. Redox Biol 11:297–311PubMedCrossRefGoogle Scholar
  79. Xu B, Zhang J, Strom J, Lee S, Chen QM (2014) Myocardial ischemic reperfusion induces de novo Nrf2 protein translation. Biochim Biophys Acta 1842:1638–1647PubMedPubMedCentralCrossRefGoogle Scholar
  80. Yang K, Huang R, Fujihira H, Suzuki T, Yan N (2018) N-glycanase NGLY1 regulates mitochondrial homeostasis and inflammation through NRF1. J Exp Med 215:2600–2616PubMedPubMedCentralCrossRefGoogle Scholar
  81. Ye P, Mimura J, Okada T, Sato H, Liu T, Maruyama A, Ohyama C, Itoh K (2014) Nrf2- and ATF4-dependent upregulation of xCT modulates the sensitivity of T24 bladder carcinoma cells to proteasome inhibition. Mol Cell Biol 34:3421–3434PubMedPubMedCentralCrossRefGoogle Scholar
  82. Yoh K, Itoh K, Enomoto A, Hirayama A, Yamaguchi N, Kobayashi M, Morito N, Koyama A, Yamamoto M, Takahashi S (2001) Nrf2-deficient female mice develop lupus-like autoimmune nephritis. Kidney Int 60:1343–1353PubMedCrossRefGoogle Scholar
  83. Zamponi E, Zamponi N, Coskun P, Quassollo G, Lorenzo A, Cannas SA, Pigino G, Chialvo DR, Gardiner K, Busciglio J, Helguera P (2018) Nrf2 stabilization prevents critical oxidative damage in Down syndrome cells. Aging Cell 17:e12812PubMedPubMedCentralCrossRefGoogle Scholar
  84. Zhang H, Davies KJA, Forman HJ (2015) Oxidative stress response and Nrf2 signaling in aging. Free Radic Biol Med 88:314–336PubMedPubMedCentralCrossRefGoogle Scholar
  85. Zhou L, Zhang H, Davies KJA, Forman HJ (2018) Aging-related decline in the induction of Nrf2-regulated antioxidant genes in human bronchial epithelial cells. Redox Biol 14:35–40PubMedCrossRefGoogle Scholar
  86. Zong ZH, Du ZX, Li N, Li C, Zhang Q, Liu BQ, Guan Y, Wang HQ (2012) Implication of Nrf2 and ATF4 in differential induction of CHOP by proteasome inhibition in thyroid cancer cells. Biochim Biophys Acta 1823:1395–1404PubMedCrossRefGoogle Scholar

Copyright information

© The Pharmaceutical Society of Korea 2019

Authors and Affiliations

  1. 1.Department of Stress Response Science, Center for Advanced Medical ResearchHirosaki University Graduate School of MedicineHirosakiJapan
  2. 2.Department of Cardiology and NephrologyHirosaki University Graduate School of MedicineHirosakiJapan

Personalised recommendations