Skip to main content
Log in

ROS and Autophagy: Interactions and Molecular Regulatory Mechanisms

  • Review Paper
  • Published:
Cellular and Molecular Neurobiology Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

References

  • Aucello M, Dobrowolny G, Musarò A (2009) Localized accumulation of oxidative stress causes muscle atrophy through activation of an autophagic pathway. Autophagy 5(4):527–529

    Article  CAS  PubMed  Google Scholar 

  • 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):2570–2581

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Bensaad K, Cheung EC, Vousden KH (2009) Modulation of intracellular ROS levels by TIGAR controls autophagy. EMBO J 28(19):3015–3026

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Chakrabarti S, Jahandideh F, Wu J (2014) Food-derived bioactive peptides on inflammation and oxidative stress. Biomed Res Int 2014:608979

    Article  PubMed Central  PubMed  Google Scholar 

  • Chen Y, Azad MB, Gibson SB (2009) Superoxide is the major reactive oxygen species regulating autophagy. Cell Death Differ 16(7):1040–1052

    Article  CAS  PubMed  Google Scholar 

  • 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):437–448

    Article  CAS  PubMed  Google Scholar 

  • 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):1210–1216

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • 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):20491–20496

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • 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):1183–1190

    Article  CAS  PubMed  Google Scholar 

  • 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):121–134

    Article  CAS  PubMed  Google Scholar 

  • 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 1853:14–26

    Article  CAS  PubMed  Google Scholar 

  • 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):1249–1258

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Giordano S, Darley-Usmar V, Zhang J (2013) Autophagy as an essential cellular antioxidant pathway in neurodegenerative disease. Redox Biol 2:82–90

    Article  PubMed Central  PubMed  Google Scholar 

  • Gurusamy N, Das DK (2009) Autophagy, redox signaling, and ventricular remodeling. Antioxid Redox Signal 11(8):1975–1988

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Hamacher-Brady A, Brady NR, Gottlieb RA (2006) Enhancing macroautophagy protects against ischemia/reperfusion injury in cardiac myocytes. J Biol Chem 281(40):29776–29787

    Article  CAS  PubMed  Google Scholar 

  • Hariharan N, Zhai P, Sadoshima J (2011) Oxidative stress stimulates autophagic flux during ischemia/reperfusion. Antioxid Redox Signal 14(11):2179–2190

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • 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):22576–22591

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • 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):444–454

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Kiffin R, Christian C (2004) Activation of chaperone-mediated autophagy during oxidative stress. Mol Biol Cell 15(11):4829–4840

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Kim I et al (2007) Selective degradation of mitochondria by mitophagy. Arch Biochem Biophys 462:245–253

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • 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):213–223

    CAS  PubMed  Google Scholar 

  • 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):252–261

    Article  PubMed  Google Scholar 

  • 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):540–550

    Article  CAS  PubMed  Google Scholar 

  • 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):784–793

    Article  CAS  PubMed  Google Scholar 

  • 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):21–31

    Article  CAS  PubMed  Google Scholar 

  • Li Lulu, Zhang Qiang, Tan Jin, Yunyun Fang Xu, An Baoyuan Chen (2014) Autophagy and hippocampal neuronal injury. Sleep Breath 18(2):243–249

    Article  PubMed  Google Scholar 

  • Mahalingaiah PK, Singh KP (2014) Chronic oxidative stress increases growth and tumorigenic potential of mcf-7 breast cancer cells. PLoS ONE 9(1):e87371

    Article  PubMed Central  PubMed  Google Scholar 

  • Massey A, Kiffin R, Cuervo AM (2004) Pathophysiology of chaperone-mediated autophagy. Int J Biochem Cell Biol 36(12):2420–2434

    Article  CAS  PubMed  Google Scholar 

  • 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):555–565

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • 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):1009–1019

    Article  CAS  PubMed  Google Scholar 

  • Puissant A, Fenouille N, Auberger P (2012) When autophagy meets cancer through p62/SQSTM1. Am J Cancer Res 2(4):397–413

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 2014:761264

    Article  PubMed Central  PubMed  Google Scholar 

  • 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):537–552

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • 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):423–438

    Article  PubMed  Google Scholar 

  • 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 67:292–303

    Article  CAS  PubMed  Google Scholar 

  • Sandri M (2013) Protein breakdown in muscle wasting: role of autophagy-lysosome and ubiquitin-proteasome. Int J Biochem Cell Biol 45(10):2121–2129

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Scherz-Shouval R, Elazar Z (2007) ROS, mitochondria and the regulation of autophagy. Trends Cell Biol 17(9):422–427

    Article  CAS  PubMed  Google Scholar 

  • Scherz-Shouval R, Elazar Z (2011) Regulation of autophagy by ROS: physiology and pathology. Trends Biochem Sci 36(1):30–38

    Article  CAS  PubMed  Google Scholar 

  • 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):1749–1760

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Semenza GL (2010) HIF-1: upstream and downstream of cancer metabolism. Curr Opin Genet Dev 20(1):51–56

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Semenza GL (2011) Hypoxia-inducible factor 1: regulator of mitochondrial metabolism and mediator of ischemic preconditioning. Biochim Biophys Acta 1813(7):1263–1268

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • 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):123–137

    Article  CAS  PubMed  Google Scholar 

  • Wilson WR, Hay MP (2011) Targeting hypoxia in cancer therapy. Nat Rev Cancer 11(6):393–410

    Article  CAS  PubMed  Google Scholar 

  • 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):300–306

    Article  CAS  PubMed  Google Scholar 

  • 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):4952–4957

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • 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):10892–10903

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • 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):376–388

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgement

This work was supported by National Natural Science Foundation of China (Grant No. 81370183), Tianjin Natural Science Foundation (Grant No. 14JCYBJC27800), and National Clinical Key Subject Construction Project of NHFPC Fund.

Conflict of interest

We confirm that all the listed authors do not have any possible conflicts of interest.

Presentation at a Conference Statement

The manuscript is an original work and has not been previously submitted or is under consideration for publication in another journal. The study complies with current ethical consideration.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Qiang Zhang.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, L., Tan, J., Miao, Y. et al. ROS and Autophagy: Interactions and Molecular Regulatory Mechanisms. Cell Mol Neurobiol 35, 615–621 (2015). https://doi.org/10.1007/s10571-015-0166-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10571-015-0166-x

Keywords

Navigation