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NAD(+) supplementation prevents STING‐induced senescence in ataxia telangiectasia by improving mitophagy

Senescence phenotypes and mitochondrial dysfunction are implicated in aging and in premature aging diseases, including ataxia telangiectasia (A‐T). Loss of mitochondrial function can drive age‐related decline in the brain, but little is known about whether improving mitochondrial homeostasis allevia...

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Autores principales: Yang, Beimeng, Dan, Xiuli, Hou, Yujun, Lee, Jong‐Hyuk, Wechter, Noah, Krishnamurthy, Sudarshan, Kimura, Risako, Babbar, Mansi, Demarest, Tyler, McDevitt, Ross, Zhang, Shiliang, Zhang, Yongqing, Mattson, Mark P., Croteau, Deborah L., Bohr, Vilhelm A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8045911/
https://www.ncbi.nlm.nih.gov/pubmed/33734555
http://dx.doi.org/10.1111/acel.13329
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author Yang, Beimeng
Dan, Xiuli
Hou, Yujun
Lee, Jong‐Hyuk
Wechter, Noah
Krishnamurthy, Sudarshan
Kimura, Risako
Babbar, Mansi
Demarest, Tyler
McDevitt, Ross
Zhang, Shiliang
Zhang, Yongqing
Mattson, Mark P.
Croteau, Deborah L.
Bohr, Vilhelm A.
author_facet Yang, Beimeng
Dan, Xiuli
Hou, Yujun
Lee, Jong‐Hyuk
Wechter, Noah
Krishnamurthy, Sudarshan
Kimura, Risako
Babbar, Mansi
Demarest, Tyler
McDevitt, Ross
Zhang, Shiliang
Zhang, Yongqing
Mattson, Mark P.
Croteau, Deborah L.
Bohr, Vilhelm A.
author_sort Yang, Beimeng
collection PubMed
description Senescence phenotypes and mitochondrial dysfunction are implicated in aging and in premature aging diseases, including ataxia telangiectasia (A‐T). Loss of mitochondrial function can drive age‐related decline in the brain, but little is known about whether improving mitochondrial homeostasis alleviates senescence phenotypes. We demonstrate here that mitochondrial dysfunction and cellular senescence with a senescence‐associated secretory phenotype (SASP) occur in A‐T patient fibroblasts, and in ATM‐deficient cells and mice. Senescence is mediated by stimulator of interferon genes (STING) and involves ectopic cytoplasmic DNA. We further show that boosting intracellular NAD(+) levels with nicotinamide riboside (NR) prevents senescence and SASP by promoting mitophagy in a PINK1‐dependent manner. NR treatment also prevents neurodegeneration, suppresses senescence and neuroinflammation, and improves motor function in Atm(−/−) mice. Our findings suggest a central role for mitochondrial dysfunction‐induced senescence in A‐T pathogenesis, and that enhancing mitophagy as a potential therapeutic intervention.
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spelling pubmed-80459112021-04-16 NAD(+) supplementation prevents STING‐induced senescence in ataxia telangiectasia by improving mitophagy Yang, Beimeng Dan, Xiuli Hou, Yujun Lee, Jong‐Hyuk Wechter, Noah Krishnamurthy, Sudarshan Kimura, Risako Babbar, Mansi Demarest, Tyler McDevitt, Ross Zhang, Shiliang Zhang, Yongqing Mattson, Mark P. Croteau, Deborah L. Bohr, Vilhelm A. Aging Cell Original Papers Senescence phenotypes and mitochondrial dysfunction are implicated in aging and in premature aging diseases, including ataxia telangiectasia (A‐T). Loss of mitochondrial function can drive age‐related decline in the brain, but little is known about whether improving mitochondrial homeostasis alleviates senescence phenotypes. We demonstrate here that mitochondrial dysfunction and cellular senescence with a senescence‐associated secretory phenotype (SASP) occur in A‐T patient fibroblasts, and in ATM‐deficient cells and mice. Senescence is mediated by stimulator of interferon genes (STING) and involves ectopic cytoplasmic DNA. We further show that boosting intracellular NAD(+) levels with nicotinamide riboside (NR) prevents senescence and SASP by promoting mitophagy in a PINK1‐dependent manner. NR treatment also prevents neurodegeneration, suppresses senescence and neuroinflammation, and improves motor function in Atm(−/−) mice. Our findings suggest a central role for mitochondrial dysfunction‐induced senescence in A‐T pathogenesis, and that enhancing mitophagy as a potential therapeutic intervention. John Wiley and Sons Inc. 2021-03-18 2021-04 /pmc/articles/PMC8045911/ /pubmed/33734555 http://dx.doi.org/10.1111/acel.13329 Text en Published 2021. This article is a U.S. Government work and is in the public domain in the USA. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd. https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Papers
Yang, Beimeng
Dan, Xiuli
Hou, Yujun
Lee, Jong‐Hyuk
Wechter, Noah
Krishnamurthy, Sudarshan
Kimura, Risako
Babbar, Mansi
Demarest, Tyler
McDevitt, Ross
Zhang, Shiliang
Zhang, Yongqing
Mattson, Mark P.
Croteau, Deborah L.
Bohr, Vilhelm A.
NAD(+) supplementation prevents STING‐induced senescence in ataxia telangiectasia by improving mitophagy
title NAD(+) supplementation prevents STING‐induced senescence in ataxia telangiectasia by improving mitophagy
title_full NAD(+) supplementation prevents STING‐induced senescence in ataxia telangiectasia by improving mitophagy
title_fullStr NAD(+) supplementation prevents STING‐induced senescence in ataxia telangiectasia by improving mitophagy
title_full_unstemmed NAD(+) supplementation prevents STING‐induced senescence in ataxia telangiectasia by improving mitophagy
title_short NAD(+) supplementation prevents STING‐induced senescence in ataxia telangiectasia by improving mitophagy
title_sort nad(+) supplementation prevents sting‐induced senescence in ataxia telangiectasia by improving mitophagy
topic Original Papers
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8045911/
https://www.ncbi.nlm.nih.gov/pubmed/33734555
http://dx.doi.org/10.1111/acel.13329
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