Skip to main content
SpringerLink
Log in

The dual role of autophagy under hypoxia-involvement of interaction between autophagy and apoptosis

  • Original Paper
  • Published:
Apoptosis Aims and scope Submit manuscript

Abstract

Hypoxia is one of severe cellular stress and it is well known to be associated with a worse outcome since a lack of oxygen accelerates the induction of apoptosis. Autophagy, an important and evolutionarily conserved mechanism for maintaining cellular homeostasis, is closely related to the apoptosis caused by hypoxia. Generally autophagy blocks the induction of apoptosis and inhibits the activation of apoptosis-associated caspase which could reduce cellular injury. However, in special cases, autophagy or autophagy-relevant proteins may help to induce apoptosis, which could aggravate cell damage under hypoxia condition. In addition, the activation of apoptosis-related proteins–caspase can also degrade autophagy-related proteins, such as Atg3, Atg4, Beclin1 protein, inhibiting autophagy. Although the relationship between autophagy and apoptosis has been known for rather complex for more than a decade, the underlying regulatory mechanisms have not been clearly understood. This short review discusses and summarizes the dual role of autophagy and the interaction and molecular regulatory mechanisms between autophagy and apoptosis under hypoxia.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Onen F, Onen H (2010) Obstructive sleep apnea and cognitive impairment in the elderly. Psychol Neuropsychiatr Vieil 8:163–169

    PubMed  Google Scholar 

  2. Wang X, Ma S, Qi G (2012) Effect of hypoxia-inducible factor 1-alpha on hypoxia/reoxygenation-induced apoptosis in primary neonatal rat cardiomyocytes. Biochem Biophys Res Commun 417:1227–1234

    Article  CAS  PubMed  Google Scholar 

  3. Yang F, Liu GS, Lu XY, Kang JL (2009) Expression of caspase-3 in rat kidney with renal tubular damage induced by lipopolysaccharide and hypoxia. Nan Fang Yi Ke Da Xue Xue Bao 29:2091–2093

    PubMed  Google Scholar 

  4. Nakka VP, Gusain A, Mehta SL, Raghubir R (2008) Molecular mechanisms of apoptosis in cerebral ischemia: multiple neuroprotective opportunities. Mol Neurobiol 37(1):7–38

    Article  CAS  PubMed  Google Scholar 

  5. Bras M, Queenan B, Susin SA (2005) Programmed cell death via mitochondria: different modes of dying. Biochem (Mosc) 70:231–239

    Article  CAS  Google Scholar 

  6. 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 29:2570–2581

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Mazure MN, Pouyssegur J (2010) Hypoxia-induced autophagy: cell death or cell survival? Curr Opin Cell Biol 22:177–180

    Article  CAS  PubMed  Google Scholar 

  8. Mariño G, Niso-Santano M, Baehrecke EH, Kroemer G (2014) Self-consumption: the interplay of autophagy and apoptosis. Nat Rev Mol Cell Biol 15:81–94

    Article  PubMed Central  PubMed  Google Scholar 

  9. Xu M, Zhang HL (2011) Death and survival of neuronal and astrocytic cells in ischemic brain injury: a role of autophagy. Acta Pharmacol Sin 32:1089–1099

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. Xia DY, Li W, Qian HR, Yao S, Liu JG, Qi XK (2013) Ischemia preconditioning is neuroprotective in a rat cerebral ischemic injury model through autophagy activation and apoptosis inhibition. Braz J Med Biol Res 46:580–588

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Kuma A, Hatano M, Matsui M, Yamamoto A, Nakaya H, Yoshimori T, Ohsumi Y, Tokuhisa T, Mizushima N (2004) The role of autophagy during the early neonatal starvation period. Nature 432:1032–1036

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. Gao L, Jiang T, Guo J, Liu Y, Cui G, Gu L, Su L, Zhang Y (2012) Inhibition of autophagy contributes to ischemic postconditioning-induced neuroprotection against focal cerebral ischemia in rats. PLoS One 7:e46092

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. Schaaf MB, Cojocari D, Keulers TG, Jutten B, Starmans MH, de Jong MC, Begg AC, Savelkouls KG, Bussink J, Vooijs M, Wouters BG, Rouschop KM (2013) The autophagy associated gene, ULK1, promotes tolerance to chronic and acute hypoxia. Radiother Oncol 108:529–534

    Article  CAS  PubMed  Google Scholar 

  15. 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  PubMed Central  CAS  PubMed  Google Scholar 

  16. Chen JL, Lin HH, Kim KJ, Lin A, Ou JH, Ann DK (2009) PKC delta signaling: a dual role in regulating hypoxic stress-induced autophagy and apoptosis. Autophagy 5(2):244–246

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. Kim J, Guan KL (2011) Regulation of the autophagy initiating kinase ULK1 by nutrients: roles of mTORC1 and AMPK. Cell Cycle 10(9):1337–1338

    Article  CAS  PubMed  Google Scholar 

  18. Cam H, Easton JB, High A, Houghton PJ (2010) mTORC1 signaling under hypoxic conditions is controlled by ATM-dependent phosphorylation of HIF-1α. Mol Cell 40(4):509–520

    Article  CAS  PubMed  Google Scholar 

  19. Papandreou I, Lim AL, Laderoute K, Denko NC (2008) Hypoxia signals autophagy in tumor cells via AMPK activity, independent of HIF-1, BNIP3, and BNIP3L. Cell Death Differ 15(10):1572–1581

    Article  CAS  PubMed  Google Scholar 

  20. Mattson MP (2000) Apoptosis in neurodegenerative disorders. Nat Rev Mol Cell Biol 1(2):120–129

    Article  CAS  PubMed  Google Scholar 

  21. Algeciras-Schimnich A, Shen L, Barnhart BC, Murmann AE, Burkhardt JK, Peter ME (2002) Molecular ordering of the initial signaling events of CD95. Mol Cell Biol 22:207–220

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  22. Adams JM (2003) Ways of dying: multiple pathways to apoptosis. Genes Dev 17:2481–2495

    Article  CAS  PubMed  Google Scholar 

  23. Ashkenazi A (2002) Targeting death and decoy receptors of the tumour-necrosis factor superfamily. Nat Rev Cancer 2:420–430

    Article  CAS  PubMed  Google Scholar 

  24. Li H, Zhu H, Xu CJ, Yuan J (1998) Cleavage of BID by caspase8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell 94:491–501

    Article  CAS  PubMed  Google Scholar 

  25. Kroemer G, Galluzzi L, Brenner C (2007) Mitochondrial membrane permeabilization in cell death. Physiol Rev 87:99–163

    Article  CAS  PubMed  Google Scholar 

  26. Tokar T, Ulicny J (2013) The mathematical model of the Bcl-2 family mediated MOMP regulation can perform a non-trivial pattern recognition. PLoS One 8(12):e81861

    Article  PubMed Central  PubMed  Google Scholar 

  27. Phesse TJ, Myant KB, Cole AM, Ridgway RA, Pearson H, Muncan V, van den Brink GR, Vousden KH, Sears R, Vassilev LT, Clarke AR, Sansom OJ (2014) Endogenous c-Myc is essential for p53-induced apoptosis in response to DNA damage in vivo. Cell Death Differ 21(6):956–966

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Gallagher PJ, Blue EK (2014) Post-translational regulation of the cellular levels of DAPK. Apoptosis 19(2):306–315

    Article  CAS  PubMed  Google Scholar 

  29. Zhang L, Wang H, Xu J, Zhu J, Ding K (2014) Inhibition of cathepsin S induces autophagy and apoptosis in human glioblastoma cell lines through ROS-mediated PI3K/AKT/mTOR/p70S6K and JNK signaling pathways. Toxicol Lett 228(3):248–259

    Article  CAS  PubMed  Google Scholar 

  30. Chen JL, Lin HH, Kim KJ, Lin A, Ou JH, Ann DK (2009) PKC delta signaling: a dual role in regulating hypoxic stress-induced autophagy and apoptosis. Autophagy 5(2):244–246

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. Li Q, Zhang T, Wang J, Zhang Z, Zhai Y, Yang GY, Sun X (2014) Rapamycin attenuates mitochondrial dysfunction via activation of mitophagy in experimental ischemic stroke. Biochem Biophys Res Commun 444(2):182–188

    Article  CAS  PubMed  Google Scholar 

  32. Zhang X, Yan H, Yuan Y, Gao J, Shen Z, Cheng Y, Shen Y, Wang RR, Wang X, Hu WW, Wang G, Chen Z (2013) Cerebral ischemia-reperfusion-induced autophagy protects against neuronal injury by mitochondrial clearance. Autophagy 9:1321–1333

    Article  CAS  PubMed  Google Scholar 

  33. Zhang R, Zhu F, Ren J, Huang L, Liu P, Wu G (2011) Beclin1/PI3K-mediated autophagy prevents hypoxia-induced apoptosis in EAhy926 cell line. Cancer Biother Radiopharm 26(3):335–343

    Article  PubMed  Google Scholar 

  34. Grishchuk Y, Ginet V, Truttmann AC, Clarke PG, Puyal J (2011) Beclin 1-independent autophagy contributes to apoptosis in cortical neurons. Autophagy 7(10):1115–1131

    Article  CAS  PubMed  Google Scholar 

  35. Grohm J, Plesnila N, Culmsee C (2010) Bid mediates fission, membrane permeabilization and peri-nuclear accumulation of mitochondria as a prerequisite for oxidative neuronal cell death. Brain Behav Immun 24(5):831–838

    Article  CAS  PubMed  Google Scholar 

  36. 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 

  37. 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 

  38. Puyal J, Vaslin A, Mottier V, Clarke PG (2009) Postischemic treatment of neonatal cerebral ischemia should target autophagy. Ann Neurol 66(3):378–389

    Article  CAS  PubMed  Google Scholar 

  39. Young MM, Takahashi Y, Khan O, Park S, Hori T, Yun J, Sharma AK, Amin S, Hu CD, Zhang J, Kester M, Wang HG (2012) Autophagosomal membrane serves as platform for intracellular death-inducing signaling complex (iDISC)-mediated caspase-8 activation and apoptosis. J Biol Chem 287:12455–12468

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  40. Russell JC, Whiting H, Szuflita N, Hossain MA (2008) Nuclear translocation of X-linked inhibitor of apoptosis (XIAP) determines cell fate after hypoxia ischemia in neonatal brain. J Neurochem 106(3):1357–1370

    Article  CAS  PubMed  Google Scholar 

  41. Nachmias B, Ashhab Y, Ben-Yehuda D (2004) The inhibitor of apoptosis protein family (IAPs): an emerging therapeutic target in cancer. Semin Cancer Biol 14:231–243

    Article  CAS  PubMed  Google Scholar 

  42. Nezis IP, Shravage BV, Sagona AP, Lamark T, Bjørkøy G, Johansen T, Rusten TE, Brech A, Baehrecke EH, Stenmark H (2010) Autophagic degradation of dBruce controls DNA fragmentation in nurse cells during late Drosophila melanogaster oogenesis. J Cell Biol 190:523–531

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  43. Mizushima N, Yoshimori T, Ohsumi Y (2011) The role of atg proteins in autophagosome formation. Annu Rev Cell Dev Biol 27:107–132

    Article  CAS  PubMed  Google Scholar 

  44. Oral O, Oz-Arslan D, Itah Z, Naghavi A, Deveci R, Karacali S, Gozuacik D (2012) Cleavage of Atg3 protein by caspase-8 regulates autophagy during receptor-activated cell death. Apoptosis 17:810–820

    Article  CAS  PubMed  Google Scholar 

  45. Kirisako T, Baba M, Ishihara N, Miyazawa K, Ohsumi M, Yoshimori T, Noda T, Ohsumi Y (1999) Formation process of autophagosome is traced with Apg8/Aut7p in yeast. J Cell Biol 147:435–446

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  46. Kim J, Huang WP, Klionsky DJ (2001) Membrane recruitment of Aut7p in the autophagy and cytoplasm to vacuole targeting pathways requires Aut1p, Aut2p, and the autophagy conjugation complex. J Cell Biol 152:51–64

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  47. Betin VM, Lane JD (2009) Caspase cleavage of Atg4D stimulates GABARAP-L1 processing and triggers mitochondrial targeting and apoptosis. J Cell Sci 122:2554–2566

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  48. Luo S, Rubinsztein DC (2010) Apoptosis blocks Beclin 1-dependent autophagosome synthesis: an effect rescued by Bcl-xL. Cell Death Differ 17:268–277

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  49. Li H, Wang P, Sun Q, Ding WX, Yin XM, Sobol RW, Stolz DB, Yu J, Zhang L (2011) Following cytochrome crelease, autophagy is inhibited during chemotherapy-induced apoptosis by caspase-8-mediated cleavage of Beclin-1. Cancer Res Cancer Res 71:3625–3634

    Article  CAS  Google Scholar 

  50. Lamy L, Ngo VN, Emre NC, Shaffer AL 3rd, Yang Y, Tian E, Nair V, Kruhlak MJ, Zingone A, Landgren O, Staudt LM (2013) Control of autophagic cell death by caspase-10 in multiple myeloma. Cancer Cell 23:435–449

    Article  PubMed Central  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

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

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Geriatrics, Tianjin Medical University General Hospital, Tianjin Geriatrics Institute, Anshan Road No. 154, Tianjin, 300052, China

    Mengmeng Li, Jin Tan, Ping Lei & Qiang Zhang

  2. Tianjin Medical University, Tianjin, China

    Yuyang Miao

Authors
  1. Mengmeng Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jin Tan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yuyang Miao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ping Lei
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Qiang Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

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, M., Tan, J., Miao, Y. et al. The dual role of autophagy under hypoxia-involvement of interaction between autophagy and apoptosis. Apoptosis 20, 769–777 (2015). https://doi.org/10.1007/s10495-015-1110-8

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10495-015-1110-8

Keywords

Search

Navigation