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Long-term HIF-1α stabilization reduces respiration, promotes mitophagy, and results in retinal cell death
Ocular hypertension during glaucoma can lead to hypoxia, activation of the HIF transcription factors, and a metabolic shift toward glycolysis. This study aims to test whether chronic HIF activation and the attendant metabolic reprogramming can initiate glaucoma-associated pathology independently of...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10667534/ https://www.ncbi.nlm.nih.gov/pubmed/37996657 http://dx.doi.org/10.1038/s41598-023-47942-8 |
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author | Nsiah, Nana Yaa Morgan, Autumn B. Donkor, Nina Inman, Denise M. |
author_facet | Nsiah, Nana Yaa Morgan, Autumn B. Donkor, Nina Inman, Denise M. |
author_sort | Nsiah, Nana Yaa |
collection | PubMed |
description | Ocular hypertension during glaucoma can lead to hypoxia, activation of the HIF transcription factors, and a metabolic shift toward glycolysis. This study aims to test whether chronic HIF activation and the attendant metabolic reprogramming can initiate glaucoma-associated pathology independently of ocular hypertension. HIF-1α stabilization was induced in mice for 2 and 4 weeks by inhibiting prolyl hydroxylases using the small molecule Roxadustat. HIF-1α stabilization and the expression of its downstream bioenergetic targets were investigated in the retina by immunofluorescence, capillary electrophoresis, and biochemical enzyme activity assays. Roxadustat dosing resulted in significant stabilization of HIF-1α in the retina by 4 weeks, and upregulation in glycolysis-associated proteins (GLUT3, PDK-1) and enzyme activity in both neurons and glia. Accordingly, succinate dehydrogenase, mitochondrial marker MTCO1, and citrate synthase activity were significantly decreased at 4 weeks, while mitophagy was significantly increased. TUNEL assay showed significant apoptosis of cells in the retina, and PERG amplitude was significantly decreased with 4 weeks of HIF-1α stabilization. A significant increase in AMPK activation and glial hypertrophy, concomitant with decreases in retinal ganglion cell function and inner retina cell death suggests that chronic HIF-1α stabilization alone is detrimental to retina metabolic homeostasis and cellular survival. |
format | Online Article Text |
id | pubmed-10667534 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-106675342023-11-23 Long-term HIF-1α stabilization reduces respiration, promotes mitophagy, and results in retinal cell death Nsiah, Nana Yaa Morgan, Autumn B. Donkor, Nina Inman, Denise M. Sci Rep Article Ocular hypertension during glaucoma can lead to hypoxia, activation of the HIF transcription factors, and a metabolic shift toward glycolysis. This study aims to test whether chronic HIF activation and the attendant metabolic reprogramming can initiate glaucoma-associated pathology independently of ocular hypertension. HIF-1α stabilization was induced in mice for 2 and 4 weeks by inhibiting prolyl hydroxylases using the small molecule Roxadustat. HIF-1α stabilization and the expression of its downstream bioenergetic targets were investigated in the retina by immunofluorescence, capillary electrophoresis, and biochemical enzyme activity assays. Roxadustat dosing resulted in significant stabilization of HIF-1α in the retina by 4 weeks, and upregulation in glycolysis-associated proteins (GLUT3, PDK-1) and enzyme activity in both neurons and glia. Accordingly, succinate dehydrogenase, mitochondrial marker MTCO1, and citrate synthase activity were significantly decreased at 4 weeks, while mitophagy was significantly increased. TUNEL assay showed significant apoptosis of cells in the retina, and PERG amplitude was significantly decreased with 4 weeks of HIF-1α stabilization. A significant increase in AMPK activation and glial hypertrophy, concomitant with decreases in retinal ganglion cell function and inner retina cell death suggests that chronic HIF-1α stabilization alone is detrimental to retina metabolic homeostasis and cellular survival. Nature Publishing Group UK 2023-11-23 /pmc/articles/PMC10667534/ /pubmed/37996657 http://dx.doi.org/10.1038/s41598-023-47942-8 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Nsiah, Nana Yaa Morgan, Autumn B. Donkor, Nina Inman, Denise M. Long-term HIF-1α stabilization reduces respiration, promotes mitophagy, and results in retinal cell death |
title | Long-term HIF-1α stabilization reduces respiration, promotes mitophagy, and results in retinal cell death |
title_full | Long-term HIF-1α stabilization reduces respiration, promotes mitophagy, and results in retinal cell death |
title_fullStr | Long-term HIF-1α stabilization reduces respiration, promotes mitophagy, and results in retinal cell death |
title_full_unstemmed | Long-term HIF-1α stabilization reduces respiration, promotes mitophagy, and results in retinal cell death |
title_short | Long-term HIF-1α stabilization reduces respiration, promotes mitophagy, and results in retinal cell death |
title_sort | long-term hif-1α stabilization reduces respiration, promotes mitophagy, and results in retinal cell death |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10667534/ https://www.ncbi.nlm.nih.gov/pubmed/37996657 http://dx.doi.org/10.1038/s41598-023-47942-8 |
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