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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....

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Autores principales: Metodieva, Vanya, Smith, Terry, Gunn-Moore, Frank
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Society for Neuroscience 2022
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.
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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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