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Organismal and Cellular Stress Responses upon Disruption of Mitochondrial Lonp1 Protease
Cells engage complex surveillance mechanisms to maintain mitochondrial function and protein homeostasis. LonP1 protease is a key component of mitochondrial quality control and has been implicated in human malignancies and other pathological disorders. Here, we employed two experimental systems, the...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9025075/ https://www.ncbi.nlm.nih.gov/pubmed/35456042 http://dx.doi.org/10.3390/cells11081363 |
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author | Taouktsi, Eirini Kyriakou, Eleni Smyrniotis, Stefanos Borbolis, Fivos Bondi, Labrina Avgeris, Socratis Trigazis, Efstathios Rigas, Stamatis Voutsinas, Gerassimos E. Syntichaki, Popi |
author_facet | Taouktsi, Eirini Kyriakou, Eleni Smyrniotis, Stefanos Borbolis, Fivos Bondi, Labrina Avgeris, Socratis Trigazis, Efstathios Rigas, Stamatis Voutsinas, Gerassimos E. Syntichaki, Popi |
author_sort | Taouktsi, Eirini |
collection | PubMed |
description | Cells engage complex surveillance mechanisms to maintain mitochondrial function and protein homeostasis. LonP1 protease is a key component of mitochondrial quality control and has been implicated in human malignancies and other pathological disorders. Here, we employed two experimental systems, the worm Caenorhabditis elegans and human cancer cells, to investigate and compare the effects of LONP-1/LonP1 deficiency at the molecular, cellular, and organismal levels. Deletion of the lonp-1 gene in worms disturbed mitochondrial function, provoked reactive oxygen species accumulation, and impaired normal processes, such as growth, behavior, and lifespan. The viability of lonp-1 mutants was dependent on the activity of the ATFS-1 transcription factor, and loss of LONP-1 evoked retrograde signaling that involved both the mitochondrial and cytoplasmic unfolded protein response (UPR(mt) and UPR(cyt)) pathways and ensuing diverse organismal stress responses. Exposure of worms to triterpenoid CDDO-Me, an inhibitor of human LonP1, stimulated only UPR(cyt) responses. In cancer cells, CDDO-Me induced key components of the integrated stress response (ISR), the UPR(mt) and UPR(cyt) pathways, and the redox machinery. However, genetic knockdown of LonP1 revealed a genotype-specific cellular response and induced apoptosis similar to CDDO-Me treatment. Overall, the mitochondrial dysfunction ensued by disruption of LonP1 elicits adaptive cytoprotective mechanisms that can inhibit cancer cell survival but diversely modulate organismal stress response and aging. |
format | Online Article Text |
id | pubmed-9025075 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-90250752022-04-23 Organismal and Cellular Stress Responses upon Disruption of Mitochondrial Lonp1 Protease Taouktsi, Eirini Kyriakou, Eleni Smyrniotis, Stefanos Borbolis, Fivos Bondi, Labrina Avgeris, Socratis Trigazis, Efstathios Rigas, Stamatis Voutsinas, Gerassimos E. Syntichaki, Popi Cells Article Cells engage complex surveillance mechanisms to maintain mitochondrial function and protein homeostasis. LonP1 protease is a key component of mitochondrial quality control and has been implicated in human malignancies and other pathological disorders. Here, we employed two experimental systems, the worm Caenorhabditis elegans and human cancer cells, to investigate and compare the effects of LONP-1/LonP1 deficiency at the molecular, cellular, and organismal levels. Deletion of the lonp-1 gene in worms disturbed mitochondrial function, provoked reactive oxygen species accumulation, and impaired normal processes, such as growth, behavior, and lifespan. The viability of lonp-1 mutants was dependent on the activity of the ATFS-1 transcription factor, and loss of LONP-1 evoked retrograde signaling that involved both the mitochondrial and cytoplasmic unfolded protein response (UPR(mt) and UPR(cyt)) pathways and ensuing diverse organismal stress responses. Exposure of worms to triterpenoid CDDO-Me, an inhibitor of human LonP1, stimulated only UPR(cyt) responses. In cancer cells, CDDO-Me induced key components of the integrated stress response (ISR), the UPR(mt) and UPR(cyt) pathways, and the redox machinery. However, genetic knockdown of LonP1 revealed a genotype-specific cellular response and induced apoptosis similar to CDDO-Me treatment. Overall, the mitochondrial dysfunction ensued by disruption of LonP1 elicits adaptive cytoprotective mechanisms that can inhibit cancer cell survival but diversely modulate organismal stress response and aging. MDPI 2022-04-16 /pmc/articles/PMC9025075/ /pubmed/35456042 http://dx.doi.org/10.3390/cells11081363 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Taouktsi, Eirini Kyriakou, Eleni Smyrniotis, Stefanos Borbolis, Fivos Bondi, Labrina Avgeris, Socratis Trigazis, Efstathios Rigas, Stamatis Voutsinas, Gerassimos E. Syntichaki, Popi Organismal and Cellular Stress Responses upon Disruption of Mitochondrial Lonp1 Protease |
title | Organismal and Cellular Stress Responses upon Disruption of Mitochondrial Lonp1 Protease |
title_full | Organismal and Cellular Stress Responses upon Disruption of Mitochondrial Lonp1 Protease |
title_fullStr | Organismal and Cellular Stress Responses upon Disruption of Mitochondrial Lonp1 Protease |
title_full_unstemmed | Organismal and Cellular Stress Responses upon Disruption of Mitochondrial Lonp1 Protease |
title_short | Organismal and Cellular Stress Responses upon Disruption of Mitochondrial Lonp1 Protease |
title_sort | organismal and cellular stress responses upon disruption of mitochondrial lonp1 protease |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9025075/ https://www.ncbi.nlm.nih.gov/pubmed/35456042 http://dx.doi.org/10.3390/cells11081363 |
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