Display options
Cite
Natarajan V, Mah T, Peishi C, et al. Oxygen Glucose Deprivation Induced Prosurvival Autophagy Is Insufficient to Rescue Endothelial Function. Front Physiol. 2020;11:533683doi: 10.3389/fphys.2020.533683.
Natarajan, V., Mah, T., Peishi, C., Tan, S. Y., Chawla, R., Arumugam, T. V., Ramasamy, A., & Mallilankaraman, K. (2020). Oxygen Glucose Deprivation Induced Prosurvival Autophagy Is Insufficient to Rescue Endothelial Function. Frontiers in physiology, 11533683. https://doi.org/10.3389/fphys.2020.533683
Natarajan, Venkateswaran, et al. "Oxygen Glucose Deprivation Induced Prosurvival Autophagy Is Insufficient to Rescue Endothelial Function." Frontiers in physiology vol. 11 (2020): 533683. doi: https://doi.org/10.3389/fphys.2020.533683
Natarajan V, Mah T, Peishi C, Tan SY, Chawla R, Arumugam TV, Ramasamy A, Mallilankaraman K. Oxygen Glucose Deprivation Induced Prosurvival Autophagy Is Insufficient to Rescue Endothelial Function. Front Physiol. 2020 Sep 16;11:533683. doi: 10.3389/fphys.2020.533683. eCollection 2020. PMID: 33041854; PMCID: PMC7526687.
Copy Download .nbib Format: NLM
Share it on

Front Physiol. 2020 Sep 16;11:533683. doi: 10.3389/fphys.2020.533683. eCollection 2020.

Oxygen Glucose Deprivation Induced Prosurvival Autophagy Is Insufficient to Rescue Endothelial Function.

Frontiers in physiology

Venkateswaran Natarajan, Tania Mah, Chen Peishi, Shu Yi Tan, Ritu Chawla, Thiruma Valavan Arumugam, Adaikalavan Ramasamy, Karthik Mallilankaraman

Affiliations

  1. Mitochondrial Physiology and Metabolism Lab, Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
  2. Department of Physiology, Anatomy and Microbiology School of Life Sciences, La Trobe University, Melbourne, VIC, Australia.
  3. Genome Institute of Singapore, ASTAR, Singapore, Singapore.
  4. Center for Healthy Longevity, NUHS, Singapore, Singapore.

PMID: 33041854 PMCID: PMC7526687 DOI: 10.3389/fphys.2020.533683

Abstract

Endothelial dysfunction, referring to a disturbance in the vascular homeostasis, has been implicated in many disease conditions including ischemic/reperfusion injury and atherosclerosis. Endothelial mitochondria have been increasingly recognized as a regulator of calcium homeostasis which has implications in the execution of diverse cellular events and energy production. The mitochondrial calcium uniporter complex through which calcium enters the mitochondria is composed of several proteins, including the pore-forming subunit MCU and its regulators MCUR1, MICU1, and MICU2. Mitochondrial calcium overload leads to opening of MPTP (mitochondrial permeability transition pore) and results in apoptotic cell death. Whereas, blockage of calcium entry into the mitochondria results in reduced ATP production thereby activates AMPK-mediated pro-survival autophagy. Here, we investigated the expression of mitochondrial calcium uniporter complex components (MCU, MCUR1, MICU1, and MICU2), induction of autophagy and apoptotic cell death in endothelial cells in response to oxygen-glucose deprivation. Human pulmonary microvascular endothelial cells (HPMVECs) were subjected to oxygen-glucose deprivation (OGD) at 3-h timepoints up to 12 h. Interestingly, except MCUR1 which was significantly downregulated, all other components of the uniporter (MCU, MICU1, and MICU2) remained unchanged. MCUR1 downregulation has been shown to activate AMPK mediated pro-survival autophagy. Similarly, MCUR1 downregulation in response to OGD resulted in AMPK phosphorylation and LC3 processing indicating the activation of pro-survival autophagy. Despite the activation of autophagy, OGD induced Caspase-mediated apoptotic cell death. Blockade of autophagy did not reduce OGD-induced apoptotic cell death whereas serum starvation conferred enough cellular and functional protection. In conclusion, the autophagic flux induced by MCUR1 downregulation in response to OGD is insufficient in protecting endothelial cells from undergoing apoptotic cell death and requires enhancement of autophagic flux by additional means such as serum starvation.

Copyright © 2020 Natarajan, Mah, Peishi, Tan, Chawla, Arumugam, Ramasamy and Mallilankaraman.

Keywords: MCUR1; apoptotic cell death; autophagy; endothelial dysfunction; oxygen-glucose deprivation

References

  1. J Physiol. 2006 Jul 1;574(Pt 1):85-93 - PubMed
  2. Nat Commun. 2016 Mar 08;7:10912 - PubMed
  3. J Korean Med Sci. 2015 Sep;30(9):1213-25 - PubMed
  4. Biochem Biophys Res Commun. 2008 May 30;370(2):230-4 - PubMed
  5. Physiol Rev. 1999 Oct;79(4):1127-55 - PubMed
  6. Curr Diab Rep. 2003 Aug;3(4):289-92 - PubMed
  7. Cell Rep. 2016 Jan 26;14(3):403-410 - PubMed
  8. Cell Metab. 2015 Oct 6;22(4):533-5 - PubMed
  9. J Physiol. 2000 Nov 15;529 Pt 1:57-68 - PubMed
  10. Annu Rev Nutr. 2007;27:19-40 - PubMed
  11. Redox Biol. 2016 Aug;8:28-42 - PubMed
  12. Cell Rep. 2017 Dec 12;21(11):3141-3154 - PubMed
  13. Nat Genet. 2014 Feb;46(2):188-93 - PubMed
  14. Nature. 2004 Jan 22;427(6972):360-4 - PubMed
  15. Front Physiol. 2019 Jan 18;10:2 - PubMed
  16. J Biol Chem. 2019 Jan 18;294(3):737-758 - PubMed
  17. Circ Res. 2007 Mar 2;100(4):460-73 - PubMed
  18. Nature. 2010 Sep 16;467(7313):291-6 - PubMed
  19. Nature. 2004 Dec 23;432(7020):1032-6 - PubMed
  20. Front Physiol. 2014 May 06;5:175 - PubMed
  21. Exp Mol Med. 2016 Apr 01;48:e224 - PubMed
  22. Science. 2013 Dec 13;342(6164):1379-82 - PubMed
  23. J Mol Cell Cardiol. 2001 Sep;33(9):1673-90 - PubMed
  24. Proteomics. 2020 Mar;20(5-6):e1800404 - PubMed
  25. Int J Mol Sci. 2018 Nov 29;19(12): - PubMed
  26. Am J Physiol Cell Physiol. 2005 Oct;289(4):C836-45 - PubMed
  27. iScience. 2020 Apr 24;23(4):101037 - PubMed
  28. Cancer Metab. 2017 Feb 2;5:3 - PubMed
  29. Proc Jpn Acad Ser B Phys Biol Sci. 2007 Mar;83(2):39-46 - PubMed
  30. Cell Death Differ. 2019 Jan;26(1):179-195 - PubMed
  31. Nature. 2011 Jun 19;476(7360):336-40 - PubMed
  32. Cell. 2012 Oct 26;151(3):630-44 - PubMed
  33. EMBO J. 2013 Aug 28;32(17):2362-76 - PubMed
  34. Elife. 2013 Jun 04;2:e00704 - PubMed
  35. Cell. 2010 Jul 23;142(2):270-83 - PubMed
  36. Cell. 2010 Feb 5;140(3):313-26 - PubMed
  37. Cell Mol Life Sci. 2014 Nov;71(21):4131-48 - PubMed
  38. Nat Cell Biol. 2012 Dec;14(12):1336-43 - PubMed
  39. Cell Calcium. 2012 Jul;52(1):28-35 - PubMed
  40. Exp Suppl. 2016;107:E1 - PubMed
  41. EMBO J. 2002 Dec 16;21(24):6744-54 - PubMed
  42. Eur Heart J. 2013 Nov;34(41):3175-81 - PubMed
  43. Biochem J. 2009 Jan 1;417(1):1-13 - PubMed
  44. Proc Natl Acad Sci U S A. 2001 Dec 18;98(26):15318-23 - PubMed
  45. Stroke. 2000 Jul;31(7):1744-51 - PubMed
  46. Nat Rev Mol Cell Biol. 2018 Feb;19(2):121-135 - PubMed
  47. Nature. 2011 Jun 19;476(7360):341-5 - PubMed
  48. Sci Rep. 2016 Nov 09;6:36570 - PubMed
  49. J Biol Chem. 2015 Feb 6;290(6):3793-802 - PubMed
  50. Cell. 2005 Jan 28;120(2):237-48 - PubMed
  51. Pflugers Arch. 2012 Jul;464(1):63-76 - PubMed
  52. Autophagy. 2018;14(8):1435-1455 - PubMed
  53. Proc Natl Acad Sci U S A. 2013 Jun 25;110(26):10479-86 - PubMed
  54. Proc Natl Acad Sci U S A. 2006 Apr 4;103(14):5379-84 - PubMed
  55. Nat Metab. 2019 Jan;1(1):158-171 - PubMed

Publication Types