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Cockayne syndrome proteins CSA and CSB maintain mitochondrial homeostasis through NAD(+) signaling
Cockayne syndrome (CS) is a rare premature aging disease, most commonly caused by mutations of the genes encoding the CSA or CSB proteins. CS patients display cachectic dwarfism and severe neurological manifestations and have an average life expectancy of 12 years. The CS proteins are involved in tr...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7744955/ https://www.ncbi.nlm.nih.gov/pubmed/33166073 http://dx.doi.org/10.1111/acel.13268 |
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author | Okur, Mustafa N. Fang, Evandro F. Fivenson, Elayne M. Tiwari, Vinod Croteau, Deborah L. Bohr, Vilhelm A. |
author_facet | Okur, Mustafa N. Fang, Evandro F. Fivenson, Elayne M. Tiwari, Vinod Croteau, Deborah L. Bohr, Vilhelm A. |
author_sort | Okur, Mustafa N. |
collection | PubMed |
description | Cockayne syndrome (CS) is a rare premature aging disease, most commonly caused by mutations of the genes encoding the CSA or CSB proteins. CS patients display cachectic dwarfism and severe neurological manifestations and have an average life expectancy of 12 years. The CS proteins are involved in transcription and DNA repair, with the latter including transcription‐coupled nucleotide excision repair (TC‐NER). However, there is also evidence for mitochondrial dysfunction in CS, which likely contributes to the severe premature aging phenotype of this disease. While damaged mitochondria and impaired mitophagy were characterized in mice with CSB deficiency, such changes in the CS nematode model and CS patients are not fully known. Our cross‐species transcriptomic analysis in CS postmortem brain tissue, CS mouse, and nematode models shows that mitochondrial dysfunction is indeed a common feature in CS. Restoration of mitochondrial dysfunction through NAD(+) supplementation significantly improved lifespan and healthspan in the CS nematodes, highlighting mitochondrial dysfunction as a major driver of the aging features of CS. In cerebellar samples from CS patients, we found molecular signatures of dysfunctional mitochondrial dynamics and impaired mitophagy/autophagy. In primary cells depleted for CSA or CSB, this dysfunction can be corrected with supplementation of NAD(+) precursors. Our study provides support for the interconnection between major causative aging theories, DNA damage accumulation, mitochondrial dysfunction, and compromised mitophagy/autophagy. Together, these three agents contribute to an accelerated aging program that can be averted by cellular NAD(+) restoration. |
format | Online Article Text |
id | pubmed-7744955 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-77449552020-12-18 Cockayne syndrome proteins CSA and CSB maintain mitochondrial homeostasis through NAD(+) signaling Okur, Mustafa N. Fang, Evandro F. Fivenson, Elayne M. Tiwari, Vinod Croteau, Deborah L. Bohr, Vilhelm A. Aging Cell Original Articles Cockayne syndrome (CS) is a rare premature aging disease, most commonly caused by mutations of the genes encoding the CSA or CSB proteins. CS patients display cachectic dwarfism and severe neurological manifestations and have an average life expectancy of 12 years. The CS proteins are involved in transcription and DNA repair, with the latter including transcription‐coupled nucleotide excision repair (TC‐NER). However, there is also evidence for mitochondrial dysfunction in CS, which likely contributes to the severe premature aging phenotype of this disease. While damaged mitochondria and impaired mitophagy were characterized in mice with CSB deficiency, such changes in the CS nematode model and CS patients are not fully known. Our cross‐species transcriptomic analysis in CS postmortem brain tissue, CS mouse, and nematode models shows that mitochondrial dysfunction is indeed a common feature in CS. Restoration of mitochondrial dysfunction through NAD(+) supplementation significantly improved lifespan and healthspan in the CS nematodes, highlighting mitochondrial dysfunction as a major driver of the aging features of CS. In cerebellar samples from CS patients, we found molecular signatures of dysfunctional mitochondrial dynamics and impaired mitophagy/autophagy. In primary cells depleted for CSA or CSB, this dysfunction can be corrected with supplementation of NAD(+) precursors. Our study provides support for the interconnection between major causative aging theories, DNA damage accumulation, mitochondrial dysfunction, and compromised mitophagy/autophagy. Together, these three agents contribute to an accelerated aging program that can be averted by cellular NAD(+) restoration. John Wiley and Sons Inc. 2020-11-09 2020-12 /pmc/articles/PMC7744955/ /pubmed/33166073 http://dx.doi.org/10.1111/acel.13268 Text en Published 2020. This article is a U.S. Government work and is in the public domain in the USA This is an open access article under the terms of the http://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 Articles Okur, Mustafa N. Fang, Evandro F. Fivenson, Elayne M. Tiwari, Vinod Croteau, Deborah L. Bohr, Vilhelm A. Cockayne syndrome proteins CSA and CSB maintain mitochondrial homeostasis through NAD(+) signaling |
title | Cockayne syndrome proteins CSA and CSB maintain mitochondrial homeostasis through NAD(+) signaling |
title_full | Cockayne syndrome proteins CSA and CSB maintain mitochondrial homeostasis through NAD(+) signaling |
title_fullStr | Cockayne syndrome proteins CSA and CSB maintain mitochondrial homeostasis through NAD(+) signaling |
title_full_unstemmed | Cockayne syndrome proteins CSA and CSB maintain mitochondrial homeostasis through NAD(+) signaling |
title_short | Cockayne syndrome proteins CSA and CSB maintain mitochondrial homeostasis through NAD(+) signaling |
title_sort | cockayne syndrome proteins csa and csb maintain mitochondrial homeostasis through nad(+) signaling |
topic | Original Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7744955/ https://www.ncbi.nlm.nih.gov/pubmed/33166073 http://dx.doi.org/10.1111/acel.13268 |
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