Oxygen Glucose Deprivation Induced Prosurvival Autophagy Is Insufficient to Rescue Endothelial Function
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 implic...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2020-09-01
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| Series: | Frontiers in Physiology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fphys.2020.533683/full |
| _version_ | 1819020952474746880 |
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| author | Venkateswaran Natarajan Tania Mah Chen Peishi Shu Yi Tan Ritu Chawla Thiruma Valavan Arumugam Adaikalavan Ramasamy Karthik Mallilankaraman Karthik Mallilankaraman |
| author_facet | Venkateswaran Natarajan Tania Mah Chen Peishi Shu Yi Tan Ritu Chawla Thiruma Valavan Arumugam Adaikalavan Ramasamy Karthik Mallilankaraman Karthik Mallilankaraman |
| author_sort | Venkateswaran Natarajan |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-21T03:59:23Z |
| format | Article |
| id | doaj.art-776886e9b90e4829bbbba36b14672d28 |
| institution | Directory Open Access Journal |
| issn | 1664-042X |
| language | English |
| last_indexed | 2024-12-21T03:59:23Z |
| publishDate | 2020-09-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Physiology |
| spelling | doaj.art-776886e9b90e4829bbbba36b14672d282022-12-21T19:16:46ZengFrontiers Media S.A.Frontiers in Physiology1664-042X2020-09-011110.3389/fphys.2020.533683533683Oxygen Glucose Deprivation Induced Prosurvival Autophagy Is Insufficient to Rescue Endothelial FunctionVenkateswaran Natarajan0Tania Mah1Chen Peishi2Shu Yi Tan3Ritu Chawla4Thiruma Valavan Arumugam5Adaikalavan Ramasamy6Karthik Mallilankaraman7Karthik Mallilankaraman8Mitochondrial Physiology and Metabolism Lab, Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, SingaporeMitochondrial Physiology and Metabolism Lab, Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, SingaporeMitochondrial Physiology and Metabolism Lab, Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, SingaporeMitochondrial Physiology and Metabolism Lab, Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, SingaporeMitochondrial Physiology and Metabolism Lab, Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, SingaporeDepartment of Physiology, Anatomy and Microbiology School of Life Sciences, La Trobe University, Melbourne, VIC, AustraliaGenome Institute of Singapore, A*STAR, Singapore, SingaporeMitochondrial Physiology and Metabolism Lab, Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, SingaporeCenter for Healthy Longevity, NUHS, Singapore, SingaporeEndothelial 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.https://www.frontiersin.org/article/10.3389/fphys.2020.533683/fullMCUR1endothelial dysfunctionoxygen-glucose deprivationautophagyapoptotic cell death |
| spellingShingle | Venkateswaran Natarajan Tania Mah Chen Peishi Shu Yi Tan Ritu Chawla Thiruma Valavan Arumugam Adaikalavan Ramasamy Karthik Mallilankaraman Karthik Mallilankaraman Oxygen Glucose Deprivation Induced Prosurvival Autophagy Is Insufficient to Rescue Endothelial Function Frontiers in Physiology MCUR1 endothelial dysfunction oxygen-glucose deprivation autophagy apoptotic cell death |
| title | Oxygen Glucose Deprivation Induced Prosurvival Autophagy Is Insufficient to Rescue Endothelial Function |
| title_full | Oxygen Glucose Deprivation Induced Prosurvival Autophagy Is Insufficient to Rescue Endothelial Function |
| title_fullStr | Oxygen Glucose Deprivation Induced Prosurvival Autophagy Is Insufficient to Rescue Endothelial Function |
| title_full_unstemmed | Oxygen Glucose Deprivation Induced Prosurvival Autophagy Is Insufficient to Rescue Endothelial Function |
| title_short | Oxygen Glucose Deprivation Induced Prosurvival Autophagy Is Insufficient to Rescue Endothelial Function |
| title_sort | oxygen glucose deprivation induced prosurvival autophagy is insufficient to rescue endothelial function |
| topic | MCUR1 endothelial dysfunction oxygen-glucose deprivation autophagy apoptotic cell death |
| url | https://www.frontiersin.org/article/10.3389/fphys.2020.533683/full |
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