Cellular and Molecular Neurobiology

, Volume 35, Issue 5, pp 615–621 | Cite as

ROS and Autophagy: Interactions and Molecular Regulatory Mechanisms

  • Lulu Li
  • Jin Tan
  • Yuyang Miao
  • Ping Lei
  • Qiang Zhang
Review Paper

Abstract

Reactive oxygen species (ROS) and antioxidant ingredients are a series of crucial signaling molecules in oxidative stress response. Under some pathological conditions such as traumatic brain injury, ischemia/reperfusion, and hypoxia in tumor, the relative excessive accumulation of ROS could break cellular homeostasis, resulting in oxidative stress and mitochondrial dysfunction. Meanwhile, autophagy is also induced. In this process, oxidative stress could promote the formation of autophagy. Autophagy, in turn, may contribute to reduce oxidative damages by engulfing and degradating oxidized substance. This short review summarizes these interactions between ROS and autophagy in related pathological conditions referred to as above with a focus on discussing internal regulatory mechanisms. The tight interactions between ROS and autophagy reflected in two aspects: the induction of autophagy by oxidative stress and the reduction of ROS by autophagy. The internal regulatory mechanisms of autophagy by ROS can be summarized as transcriptional and post-transcriptional regulation, which includes various molecular signal pathways such as ROS–FOXO3–LC3/BNIP3–autophagy, ROS–NRF2–P62–autophagy, ROS–HIF1–BNIP3/NIX–autophagy, and ROS–TIGAR–autophagy. Autophagy also may regulate ROS levels through several pathways such as chaperone-mediated autophagy pathway, mitophagy pathway, and P62 delivery pathway, which might provide a further theoretical basis for the pathogenesis of the related diseases and still need further research.

Keywords

Reactive oxygen species (ROS) Oxidative stress Autophagy Traumatic brain injury (TBI) Ischemia/reperfusion (I/R) Tumor 

References

  1. Aucello M, Dobrowolny G, Musarò A (2009) Localized accumulation of oxidative stress causes muscle atrophy through activation of an autophagic pathway. Autophagy 5(4):527–529CrossRefPubMedGoogle Scholar
  2. Bellot G, Garcia-Medina R, Gounon P, Chiche J, Roux D, Pouysségur J, Mazure NM (2009) Hypoxia-induced autophagy is mediated through hypoxia-inducible factor induction of BNIP3 and BNIP3L via their BH3 domains. Mol Cell Biol 29(10):2570–2581PubMedCentralCrossRefPubMedGoogle Scholar
  3. Bensaad K, Cheung EC, Vousden KH (2009) Modulation of intracellular ROS levels by TIGAR controls autophagy. EMBO J 28(19):3015–3026PubMedCentralCrossRefPubMedGoogle Scholar
  4. Chakrabarti S, Jahandideh F, Wu J (2014) Food-derived bioactive peptides on inflammation and oxidative stress. Biomed Res Int 2014:608979PubMedCentralCrossRefPubMedGoogle Scholar
  5. Chen Y, Azad MB, Gibson SB (2009) Superoxide is the major reactive oxygen species regulating autophagy. Cell Death Differ 16(7):1040–1052CrossRefPubMedGoogle Scholar
  6. Chen G, Zhang W, Li YP, Ren JG, Xu N, Liu H, Wang FQ, Sun ZJ, Jia J, Zhao YF (2013) Hypoxia-induced autophagy in endothelial cells: a double-edged sword in the progression of infantile haemangioma? Cardiovasc Res 98(3):437–448CrossRefPubMedGoogle Scholar
  7. Chen W, Sun Y, Liu K, Sun X (2014) Autophagy: a double-edged sword for neuronal survival after cerebral ischemia. Neural Regen Res 9(12):1210–1216PubMedCentralCrossRefPubMedGoogle Scholar
  8. Cheung EC, Ludwig RL, Vousden KH (2012) Mitochondrial localization of TIGAR under hypoxia stimulates HK2 and lowers ROS and cell death. Proc Natl Acad Sci U S A 109(50):20491–20496PubMedCentralCrossRefPubMedGoogle Scholar
  9. Chien CT, Shyue SK, Lai MK (2007) Bcl-xL augmentation potentially reduces ischemia/reperfusion induced proximal and distal tubular apoptosis and autophagy. Transplantation 84(9):1183–1190CrossRefPubMedGoogle Scholar
  10. Crighton D, Wilkinson S, O’Prey J, Syed N, Smith P, Harrison PR, Gasco M, Garrone O, Crook T, Ryan KM (2006) DRAM, a p53-induced modulator of autophagy, is critical for apoptosis. Cell 126(1):121–134CrossRefPubMedGoogle Scholar
  11. Evangelisti C, Evangelisti C, Chiarini F, Lonetti A, Buontempo F, Neri LM, McCubrey JA, Martelli AM (2015) Autophagy in acute leukemias: a double-edged sword with important therapeutic implications. Biochim Biophys Acta 1853:14–26CrossRefPubMedGoogle Scholar
  12. Fandy TE, Jiemjit A, Thakar M, Rhoden P, Suarez L, Gore SD (2014) Decitabine induces delayed reactive oxygen species (ROS) accumulation in leukemia cells and induces the expression of ROS generating enzymes. Clin Cancer Res 20(5):1249–1258PubMedCentralCrossRefPubMedGoogle Scholar
  13. Giordano S, Darley-Usmar V, Zhang J (2013) Autophagy as an essential cellular antioxidant pathway in neurodegenerative disease. Redox Biol 2:82–90PubMedCentralCrossRefPubMedGoogle Scholar
  14. Gurusamy N, Das DK (2009) Autophagy, redox signaling, and ventricular remodeling. Antioxid Redox Signal 11(8):1975–1988PubMedCentralCrossRefPubMedGoogle Scholar
  15. Hamacher-Brady A, Brady NR, Gottlieb RA (2006) Enhancing macroautophagy protects against ischemia/reperfusion injury in cardiac myocytes. J Biol Chem 281(40):29776–29787CrossRefPubMedGoogle Scholar
  16. Hariharan N, Zhai P, Sadoshima J (2011) Oxidative stress stimulates autophagic flux during ischemia/reperfusion. Antioxid Redox Signal 14(11):2179–2190PubMedCentralCrossRefPubMedGoogle Scholar
  17. Jain A, Lamark T, Sjøttem E, Larsen KB, Awuh JA, Øvervatn A, McMahon M, Hayes JD, Johansen T (2010) 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(29):22576–22591PubMedCentralCrossRefPubMedGoogle Scholar
  18. Kaushik S, Cuervo AM (2006) Autophagy as a cell-repair mechanism: activation of chaperone-mediated autophagy during oxidative stress. Mol Aspects Med 27(5–6):444–454PubMedCentralCrossRefPubMedGoogle Scholar
  19. Kiffin R, Christian C (2004) Activation of chaperone-mediated autophagy during oxidative stress. Mol Biol Cell 15(11):4829–4840PubMedCentralCrossRefPubMedGoogle Scholar
  20. Kim I et al (2007) Selective degradation of mitochondria by mitophagy. Arch Biochem Biophys 462:245–253PubMedCentralCrossRefPubMedGoogle Scholar
  21. Komatsu M, Kurokawa H, Waguri S, Taguchi K, Kobayashi A, Ichimura Y, Sou YS, Ueno I, Sakamoto A, Tong KI, Kim M, Nishito Y, Iemura S, Natsume T, Ueno T, Kominami E, Motohashi H, Tanaka K, Yamamoto M (2010) The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1. Nat Cell Biol 12(3):213–223PubMedGoogle Scholar
  22. Koritzinsky M, Wouters BG (2013) The roles of reactive oxygen species and autophagy in mediating the tolerance of tumor cells to cycling hypoxia. Semin Radiat Oncol 23(4):252–261CrossRefPubMedGoogle Scholar
  23. Lai Y, Hickey RW, Chen Y, Bayir H, Sullivan ML, Chu CT, Kochanek PM, Dixon CE, Jenkins LW, Graham SH, Watkins SC, Clark RS (2008) Autophagy is increased after traumatic brain injury in mice and is partially inhibited by the antioxidant gamma-glutamylcysteinyl ethyl ester. J Cereb Blood Flow Metab 28(3):540–550CrossRefPubMedGoogle Scholar
  24. Larsen KB, Lamark T, Øvervatn A, Harneshaug I, Johansen T, Bjørkøy G (2010) A reporter cell system to monitor autophagy based on p62/SQSTM1. Autophagy 6(6):784–793CrossRefPubMedGoogle Scholar
  25. Li Y, Luo Q, Yuan L, Miao C, Mu X, Xiao W, Li J, Sun T, Ma E (2012) JNK-dependent Atg4 upregulation mediates asperphenamate derivative BBP-induced autophagy in MCF-7 cells. Toxicol Appl Pharmacol 263(1):21–31CrossRefPubMedGoogle Scholar
  26. Li Lulu, Zhang Qiang, Tan Jin, Yunyun Fang Xu, An Baoyuan Chen (2014) Autophagy and hippocampal neuronal injury. Sleep Breath 18(2):243–249CrossRefPubMedGoogle Scholar
  27. Mahalingaiah PK, Singh KP (2014) Chronic oxidative stress increases growth and tumorigenic potential of mcf-7 breast cancer cells. PLoS ONE 9(1):e87371PubMedCentralCrossRefPubMedGoogle Scholar
  28. Massey A, Kiffin R, Cuervo AM (2004) Pathophysiology of chaperone-mediated autophagy. Int J Biochem Cell Biol 36(12):2420–2434CrossRefPubMedGoogle Scholar
  29. Mortiboys H, Thomas KJ, Koopman WJ, Klaffke S, Abou-Sleiman P, Olpin S, Wood NW, Willems PH, Smeitink JA, Cookson MR, Bandmann O (2008) Mitochondrial function and morphology are impaired in parkin-mutant fibroblasts. Ann Neurol 64(5):555–565PubMedCentralCrossRefPubMedGoogle Scholar
  30. Oh SH, Kim YS, Lim SC, Hou YF, Chang IY, You HJ (2008) Dihydrocapsaicin (DHC), a saturated structural analog of capsaicin, induces autophagy in human cancer cells in a catalase-regulated manner. Autophagy 4(8):1009–1019CrossRefPubMedGoogle Scholar
  31. Puissant A, Fenouille N, Auberger P (2012) When autophagy meets cancer through p62/SQSTM1. Am J Cancer Res 2(4):397–413PubMedCentralPubMedGoogle Scholar
  32. Rahal A, Kumar A, Singh V, Yadav B, Tiwari R, Chakraborty S, Dhama K (2014) Oxidative stress, prooxidants, and antioxidants: the interplay. Biomed Res Int 2014:761264PubMedCentralCrossRefPubMedGoogle Scholar
  33. Riley BE, Kaiser SE, Shaler TA, Ng AC, Hara T, Hipp MS, Lage K, Xavier RJ, Ryu KY, Taguchi K, Yamamoto M, Tanaka K, Mizushima N, Komatsu M, Kopito RR (2010) Ubiquitin accumulation in autophagy-deficient mice is dependent on the Nrf2-mediated stress response pathway: a potential role for protein aggregation in autophagic substrate selection. J Cell Biol 191(3):537–552PubMedCentralCrossRefPubMedGoogle Scholar
  34. Rodríguez-Navarro JA, Rodríguez L, Casarejos MJ, Solano RM, Gómez A, Perucho J, Cuervo AM, García de Yébenes J, Mena MA (2010) Trehalose ameliorates dopaminergic and tau pathology in parkin deleted/tau overexpressing mice through autophagy activation. Neurobiol Dis 39(3):423–438CrossRefPubMedGoogle Scholar
  35. Rubio N, Verrax J, Dewaele M, Verfaillie T, Johansen T, Piette J, Agostinis P (2014) p38(MAPK)-regulated induction of p62 and NBR1 after photodynamic therapy promotes autophagic clearance of ubiquitin aggregates and reduces reactive oxygen species levels by supporting Nrf2-antioxidant signaling. Free Radic Biol Med 67:292–303CrossRefPubMedGoogle Scholar
  36. Sandri M (2013) Protein breakdown in muscle wasting: role of autophagy-lysosome and ubiquitin-proteasome. Int J Biochem Cell Biol 45(10):2121–2129PubMedCentralCrossRefPubMedGoogle Scholar
  37. Scherz-Shouval R, Elazar Z (2007) ROS, mitochondria and the regulation of autophagy. Trends Cell Biol 17(9):422–427CrossRefPubMedGoogle Scholar
  38. Scherz-Shouval R, Elazar Z (2011) Regulation of autophagy by ROS: physiology and pathology. Trends Biochem Sci 36(1):30–38CrossRefPubMedGoogle Scholar
  39. Scherz-Shouval R, Shvets E, Fass E, Shorer H, Gil L, Elazar Z (2007) Reactive oxygen species are essential for autophagy and specifically regulate the activity of Atg4. EMBO J 26(7):1749–1760PubMedCentralCrossRefPubMedGoogle Scholar
  40. Semenza GL (2010) HIF-1: upstream and downstream of cancer metabolism. Curr Opin Genet Dev 20(1):51–56PubMedCentralCrossRefPubMedGoogle Scholar
  41. Semenza GL (2011) Hypoxia-inducible factor 1: regulator of mitochondrial metabolism and mediator of ischemic preconditioning. Biochim Biophys Acta 1813(7):1263–1268PubMedCentralCrossRefPubMedGoogle Scholar
  42. Ureshino RP, Rocha KK, Lopes GS, Trindade CB, Smaili SS (2014) Calcium signaling alterations, oxidative stress and autophagy in aging. Antioxid Redox Signal 21(1):123–137CrossRefPubMedGoogle Scholar
  43. Wilson WR, Hay MP (2011) Targeting hypoxia in cancer therapy. Nat Rev Cancer 11(6):393–410CrossRefPubMedGoogle Scholar
  44. Ye L, Zhao X, Lu J, Qian G, Zheng JC, Ge S (2013) Knockdown of TIGAR by RNA interference induces apoptosis and autophagy in HepG2 hepatocellular carcinoma cells. Biochem Biophys Res Commun 437(2):300–306CrossRefPubMedGoogle Scholar
  45. Yu L, Wan F, Dutta S, Welsh S, Liu Z, Freundt E, Baehrecke EH, Lenardo M (2006) Autophagic programmed cell death by selective catalase degradation. Proc Natl Acad Sci U S A 103(13):4952–4957PubMedCentralCrossRefPubMedGoogle Scholar
  46. Zhang H, Bosch-Marce M, Shimoda LA, Tan YS, Baek JH, Wesley JB, Gonzalez FJ, Semenza GL (2008) Mitochondrial autophagy is an HIF-1-dependent adaptive metabolic response to hypoxia. J Biol Chem 283(16):10892–10903PubMedCentralCrossRefPubMedGoogle Scholar
  47. Zhang H, Kong X, Kang J, Su J, Li Y, Zhong J, Sun L (2009) Oxidative stress induces parallel autophagy and mitochondria dysfunction in human glioma U251 cells. Toxicol Sci 110(2):376–388CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Lulu Li
    • 1
  • Jin Tan
    • 1
  • Yuyang Miao
    • 2
  • Ping Lei
    • 1
  • Qiang Zhang
    • 1
  1. 1.Department of GeriatricsTianjin Medical University General Hospital, Tianjin Geriatrics InstituteTianjinChina
  2. 2.Tianjin Medical UniversityTianjinChina

Personalised recommendations