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The Mitochondrial Enzyme 17βHSD10 Modulates Ischemic and Amyloid-β-Induced Stress in Primary Mouse Astrocytes
Severe brain metabolic dysfunction and amyloid-β accumulation are key hallmarks of Alzheimer’s disease (AD). While astrocytes contribute to both pathologic mechanisms, the role of their mitochondria, which is essential for signaling and maintenance of these processes, has been largely understudied....
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Society for Neuroscience
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9536859/ https://www.ncbi.nlm.nih.gov/pubmed/36096650 http://dx.doi.org/10.1523/ENEURO.0040-22.2022 |
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author | Metodieva, Vanya Smith, Terry Gunn-Moore, Frank |
author_facet | Metodieva, Vanya Smith, Terry Gunn-Moore, Frank |
author_sort | Metodieva, Vanya |
collection | PubMed |
description | Severe brain metabolic dysfunction and amyloid-β accumulation are key hallmarks of Alzheimer’s disease (AD). While astrocytes contribute to both pathologic mechanisms, the role of their mitochondria, which is essential for signaling and maintenance of these processes, has been largely understudied. The current work provides the first direct evidence that the mitochondrial metabolic switch 17β-hydroxysteroid dehydrogenase type 10 (17βHSD10) is expressed and active in murine astrocytes from different brain regions. While it is known that this protein is overexpressed in the brains of AD patients, we found that 17βHSD10 is also upregulated in astrocytes exposed to amyloidogenic and ischemic stress. Importantly, such catalytic overexpression of 17βHSD10 inhibits mitochondrial respiration during increased energy demand. This observation contrasts with what has been found in neuronal and cancer model systems, which suggests astrocyte-specific mechanisms mediated by the protein. Furthermore, the catalytic upregulation of the enzyme exacerbates astrocytic damage, reactive oxygen species (ROS) generation and mitochondrial network alterations during amyloidogenic stress. On the other hand, 17βHSD10 inhibition through AG18051 counters most of these effects. In conclusion, our data represents novel insights into the role of astrocytic mitochondria in metabolic and amyloidogenic stress with implications of 17βHSD10 in multiple neurodegenerative mechanisms. |
format | Online Article Text |
id | pubmed-9536859 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Society for Neuroscience |
record_format | MEDLINE/PubMed |
spelling | pubmed-95368592022-10-11 The Mitochondrial Enzyme 17βHSD10 Modulates Ischemic and Amyloid-β-Induced Stress in Primary Mouse Astrocytes Metodieva, Vanya Smith, Terry Gunn-Moore, Frank eNeuro Research Article: New Research Severe brain metabolic dysfunction and amyloid-β accumulation are key hallmarks of Alzheimer’s disease (AD). While astrocytes contribute to both pathologic mechanisms, the role of their mitochondria, which is essential for signaling and maintenance of these processes, has been largely understudied. The current work provides the first direct evidence that the mitochondrial metabolic switch 17β-hydroxysteroid dehydrogenase type 10 (17βHSD10) is expressed and active in murine astrocytes from different brain regions. While it is known that this protein is overexpressed in the brains of AD patients, we found that 17βHSD10 is also upregulated in astrocytes exposed to amyloidogenic and ischemic stress. Importantly, such catalytic overexpression of 17βHSD10 inhibits mitochondrial respiration during increased energy demand. This observation contrasts with what has been found in neuronal and cancer model systems, which suggests astrocyte-specific mechanisms mediated by the protein. Furthermore, the catalytic upregulation of the enzyme exacerbates astrocytic damage, reactive oxygen species (ROS) generation and mitochondrial network alterations during amyloidogenic stress. On the other hand, 17βHSD10 inhibition through AG18051 counters most of these effects. In conclusion, our data represents novel insights into the role of astrocytic mitochondria in metabolic and amyloidogenic stress with implications of 17βHSD10 in multiple neurodegenerative mechanisms. Society for Neuroscience 2022-10-05 /pmc/articles/PMC9536859/ /pubmed/36096650 http://dx.doi.org/10.1523/ENEURO.0040-22.2022 Text en Copyright © 2022 Metodieva et al. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed. |
spellingShingle | Research Article: New Research Metodieva, Vanya Smith, Terry Gunn-Moore, Frank The Mitochondrial Enzyme 17βHSD10 Modulates Ischemic and Amyloid-β-Induced Stress in Primary Mouse Astrocytes |
title | The Mitochondrial Enzyme 17βHSD10 Modulates Ischemic and Amyloid-β-Induced Stress in Primary Mouse Astrocytes |
title_full | The Mitochondrial Enzyme 17βHSD10 Modulates Ischemic and Amyloid-β-Induced Stress in Primary Mouse Astrocytes |
title_fullStr | The Mitochondrial Enzyme 17βHSD10 Modulates Ischemic and Amyloid-β-Induced Stress in Primary Mouse Astrocytes |
title_full_unstemmed | The Mitochondrial Enzyme 17βHSD10 Modulates Ischemic and Amyloid-β-Induced Stress in Primary Mouse Astrocytes |
title_short | The Mitochondrial Enzyme 17βHSD10 Modulates Ischemic and Amyloid-β-Induced Stress in Primary Mouse Astrocytes |
title_sort | mitochondrial enzyme 17βhsd10 modulates ischemic and amyloid-β-induced stress in primary mouse astrocytes |
topic | Research Article: New Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9536859/ https://www.ncbi.nlm.nih.gov/pubmed/36096650 http://dx.doi.org/10.1523/ENEURO.0040-22.2022 |
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