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SIRT3 deficiency-induced mitochondrial dysfunction and inflammasome formation in the brain

SIRT3, the primary mitochondrial deacetylase, plays a significant role in enhancing the function of mitochondrial proteins. Downregulation of SIRT3 is a key component of metabolic syndrome, a precondition for obesity, diabetes and cardiovascular diseases. In this study, we examined the effects of br...

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Autores principales: Tyagi, Alpna, Nguyen, Christy U, Chong, Thomas, Michel, Cole R, Fritz, Kristofer S., Reisdorph, Nichole, Knaub, Leslie, Reusch, Jane E. B., Pugazhenthi, Subbiah
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6277395/
https://www.ncbi.nlm.nih.gov/pubmed/30510203
http://dx.doi.org/10.1038/s41598-018-35890-7
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author Tyagi, Alpna
Nguyen, Christy U
Chong, Thomas
Michel, Cole R
Fritz, Kristofer S.
Reisdorph, Nichole
Knaub, Leslie
Reusch, Jane E. B.
Pugazhenthi, Subbiah
author_facet Tyagi, Alpna
Nguyen, Christy U
Chong, Thomas
Michel, Cole R
Fritz, Kristofer S.
Reisdorph, Nichole
Knaub, Leslie
Reusch, Jane E. B.
Pugazhenthi, Subbiah
author_sort Tyagi, Alpna
collection PubMed
description SIRT3, the primary mitochondrial deacetylase, plays a significant role in enhancing the function of mitochondrial proteins. Downregulation of SIRT3 is a key component of metabolic syndrome, a precondition for obesity, diabetes and cardiovascular diseases. In this study, we examined the effects of brain mitochondrial protein hyperacetylation in western diet-fed Sirt3(−/−) mice, a model for metabolic syndrome. Brain mitochondrial proteins were hyperacetylated, following western diet feeding and Sirt3 deletion. To identity these hyperacetylated proteins, we performed a comprehensive acetylome analysis by label-free tandem mass spectrometry. Gene ontology pathway analysis revealed Sirt3 deletion-mediated downregulation of enzymes in several metabolic pathways, including fatty acid oxidation and tricarboxylic acid cycle. Mitochondrial respiration was impaired at multiple states, along with lower levels of mitochondrial fission proteins Mfn1 and Mfn2. Cleavage of procaspase-1 suggested inflammasome formation. Assembly of inflammasomes with caspase-1 and NLRP3 was detected as shown by proximity ligation assay. Markers of neuroinflammation including microgliosis and elevated brain IL-1β expression were also observed. Importantly, these findings were further exacerbated in Sirt3(−/−) mice when fed a calorie-rich western diet. The observations of this study suggest that SIRT3 deficiency-induced brain mitochondrial dysfunction and neuroinflammation in metabolic syndrome may play a role in late-life cognitive decline.
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spelling pubmed-62773952018-12-06 SIRT3 deficiency-induced mitochondrial dysfunction and inflammasome formation in the brain Tyagi, Alpna Nguyen, Christy U Chong, Thomas Michel, Cole R Fritz, Kristofer S. Reisdorph, Nichole Knaub, Leslie Reusch, Jane E. B. Pugazhenthi, Subbiah Sci Rep Article SIRT3, the primary mitochondrial deacetylase, plays a significant role in enhancing the function of mitochondrial proteins. Downregulation of SIRT3 is a key component of metabolic syndrome, a precondition for obesity, diabetes and cardiovascular diseases. In this study, we examined the effects of brain mitochondrial protein hyperacetylation in western diet-fed Sirt3(−/−) mice, a model for metabolic syndrome. Brain mitochondrial proteins were hyperacetylated, following western diet feeding and Sirt3 deletion. To identity these hyperacetylated proteins, we performed a comprehensive acetylome analysis by label-free tandem mass spectrometry. Gene ontology pathway analysis revealed Sirt3 deletion-mediated downregulation of enzymes in several metabolic pathways, including fatty acid oxidation and tricarboxylic acid cycle. Mitochondrial respiration was impaired at multiple states, along with lower levels of mitochondrial fission proteins Mfn1 and Mfn2. Cleavage of procaspase-1 suggested inflammasome formation. Assembly of inflammasomes with caspase-1 and NLRP3 was detected as shown by proximity ligation assay. Markers of neuroinflammation including microgliosis and elevated brain IL-1β expression were also observed. Importantly, these findings were further exacerbated in Sirt3(−/−) mice when fed a calorie-rich western diet. The observations of this study suggest that SIRT3 deficiency-induced brain mitochondrial dysfunction and neuroinflammation in metabolic syndrome may play a role in late-life cognitive decline. Nature Publishing Group UK 2018-12-03 /pmc/articles/PMC6277395/ /pubmed/30510203 http://dx.doi.org/10.1038/s41598-018-35890-7 Text en © The Author(s) 2018 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Tyagi, Alpna
Nguyen, Christy U
Chong, Thomas
Michel, Cole R
Fritz, Kristofer S.
Reisdorph, Nichole
Knaub, Leslie
Reusch, Jane E. B.
Pugazhenthi, Subbiah
SIRT3 deficiency-induced mitochondrial dysfunction and inflammasome formation in the brain
title SIRT3 deficiency-induced mitochondrial dysfunction and inflammasome formation in the brain
title_full SIRT3 deficiency-induced mitochondrial dysfunction and inflammasome formation in the brain
title_fullStr SIRT3 deficiency-induced mitochondrial dysfunction and inflammasome formation in the brain
title_full_unstemmed SIRT3 deficiency-induced mitochondrial dysfunction and inflammasome formation in the brain
title_short SIRT3 deficiency-induced mitochondrial dysfunction and inflammasome formation in the brain
title_sort sirt3 deficiency-induced mitochondrial dysfunction and inflammasome formation in the brain
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6277395/
https://www.ncbi.nlm.nih.gov/pubmed/30510203
http://dx.doi.org/10.1038/s41598-018-35890-7
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