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LON is the master protease that protects against protein aggregation in human mitochondria through direct degradation of misfolded proteins
Maintenance of mitochondrial protein homeostasis is critical for proper cellular function. Under normal conditions resident molecular chaperones and proteases maintain protein homeostasis within the organelle. Under conditions of stress however, misfolded proteins accumulate leading to the activatio...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4667172/ https://www.ncbi.nlm.nih.gov/pubmed/26627475 http://dx.doi.org/10.1038/srep17397 |
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author | Bezawork-Geleta, Ayenachew Brodie, Erica J. Dougan, David A. Truscott, Kaye N. |
author_facet | Bezawork-Geleta, Ayenachew Brodie, Erica J. Dougan, David A. Truscott, Kaye N. |
author_sort | Bezawork-Geleta, Ayenachew |
collection | PubMed |
description | Maintenance of mitochondrial protein homeostasis is critical for proper cellular function. Under normal conditions resident molecular chaperones and proteases maintain protein homeostasis within the organelle. Under conditions of stress however, misfolded proteins accumulate leading to the activation of the mitochondrial unfolded protein response (UPR(mt)). While molecular chaperone assisted refolding of proteins in mammalian mitochondria has been well documented, the contribution of AAA+ proteases to the maintenance of protein homeostasis in this organelle remains unclear. To address this gap in knowledge we examined the contribution of human mitochondrial matrix proteases, LONM and CLPXP, to the turnover of OTC-∆, a folding incompetent mutant of ornithine transcarbamylase, known to activate UPR(mt). Contrary to a model whereby CLPXP is believed to degrade misfolded proteins, we found that LONM, and not CLPXP is responsible for the turnover of OTC-∆ in human mitochondria. To analyse the conformational state of proteins that are recognised by LONM, we examined the turnover of unfolded and aggregated forms of malate dehydrogenase (MDH) and OTC. This analysis revealed that LONM specifically recognises and degrades unfolded, but not aggregated proteins. Since LONM is not upregulated by UPR(mt), this pathway may preferentially act to promote chaperone mediated refolding of proteins. |
format | Online Article Text |
id | pubmed-4667172 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-46671722015-12-03 LON is the master protease that protects against protein aggregation in human mitochondria through direct degradation of misfolded proteins Bezawork-Geleta, Ayenachew Brodie, Erica J. Dougan, David A. Truscott, Kaye N. Sci Rep Article Maintenance of mitochondrial protein homeostasis is critical for proper cellular function. Under normal conditions resident molecular chaperones and proteases maintain protein homeostasis within the organelle. Under conditions of stress however, misfolded proteins accumulate leading to the activation of the mitochondrial unfolded protein response (UPR(mt)). While molecular chaperone assisted refolding of proteins in mammalian mitochondria has been well documented, the contribution of AAA+ proteases to the maintenance of protein homeostasis in this organelle remains unclear. To address this gap in knowledge we examined the contribution of human mitochondrial matrix proteases, LONM and CLPXP, to the turnover of OTC-∆, a folding incompetent mutant of ornithine transcarbamylase, known to activate UPR(mt). Contrary to a model whereby CLPXP is believed to degrade misfolded proteins, we found that LONM, and not CLPXP is responsible for the turnover of OTC-∆ in human mitochondria. To analyse the conformational state of proteins that are recognised by LONM, we examined the turnover of unfolded and aggregated forms of malate dehydrogenase (MDH) and OTC. This analysis revealed that LONM specifically recognises and degrades unfolded, but not aggregated proteins. Since LONM is not upregulated by UPR(mt), this pathway may preferentially act to promote chaperone mediated refolding of proteins. Nature Publishing Group 2015-12-02 /pmc/articles/PMC4667172/ /pubmed/26627475 http://dx.doi.org/10.1038/srep17397 Text en Copyright © 2015, Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
spellingShingle | Article Bezawork-Geleta, Ayenachew Brodie, Erica J. Dougan, David A. Truscott, Kaye N. LON is the master protease that protects against protein aggregation in human mitochondria through direct degradation of misfolded proteins |
title | LON is the master protease that protects against protein aggregation in human mitochondria through direct degradation of misfolded proteins |
title_full | LON is the master protease that protects against protein aggregation in human mitochondria through direct degradation of misfolded proteins |
title_fullStr | LON is the master protease that protects against protein aggregation in human mitochondria through direct degradation of misfolded proteins |
title_full_unstemmed | LON is the master protease that protects against protein aggregation in human mitochondria through direct degradation of misfolded proteins |
title_short | LON is the master protease that protects against protein aggregation in human mitochondria through direct degradation of misfolded proteins |
title_sort | lon is the master protease that protects against protein aggregation in human mitochondria through direct degradation of misfolded proteins |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4667172/ https://www.ncbi.nlm.nih.gov/pubmed/26627475 http://dx.doi.org/10.1038/srep17397 |
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