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Mitochondrial carrier protein overloading and misfolding induce aggresomes and proteostatic adaptations in the cytosol
Previous studies in yeast showed that mitochondrial stressors not directly targeting the protein import machinery can cause mitochondrial precursor overaccumulation stress (mPOS) in the cytosol independent of bioenergetics. Here, we demonstrate mPOS and stress responses in human cells. We show that...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The American Society for Cell Biology
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6724602/ https://www.ncbi.nlm.nih.gov/pubmed/30893019 http://dx.doi.org/10.1091/mbc.E19-01-0046 |
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author | Liu, Yaxin Wang, Xiaowen Coyne, Liam P. Yang, Yuan Qi, Yue Middleton, Frank A. Chen, Xin Jie |
author_facet | Liu, Yaxin Wang, Xiaowen Coyne, Liam P. Yang, Yuan Qi, Yue Middleton, Frank A. Chen, Xin Jie |
author_sort | Liu, Yaxin |
collection | PubMed |
description | Previous studies in yeast showed that mitochondrial stressors not directly targeting the protein import machinery can cause mitochondrial precursor overaccumulation stress (mPOS) in the cytosol independent of bioenergetics. Here, we demonstrate mPOS and stress responses in human cells. We show that overloading of mitochondrial membrane carrier, but not matrix proteins, is sufficient to induce cytosolic aggresomes and apoptosis. The aggresomes appear to triage unimported mitochondrial proteins. Interestingly, expression of highly unstable mutant variants of the mitochondrial carrier protein, Ant1, also induces aggresomes despite a greater than 20-fold reduction in protein level compared to wild type. Thus, overloading of the protein import machinery, rather than protein accumulation, is critical for aggresome induction. The data suggest that the import of mitochondrial proteins is saturable and that the cytosol is limited in degrading unimported mitochondrial proteins. In addition, we found that EGR1, eEF1a, and ubiquitin C are up-regulated by Ant1 overloading. These proteins are known to promote autophagy, protein targeting to aggresomes, and the processing of protein aggregates, respectively. Finally, we found that overexpression of the misfolded variants of Ant1 induces additional cytosolic responses including proteasomal activation. In summary, our work captured a profound effect of unimported mitochondrial proteins on cytosolic proteostasis and revealed multiple anti-mPOS mechanisms in human cells. |
format | Online Article Text |
id | pubmed-6724602 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | The American Society for Cell Biology |
record_format | MEDLINE/PubMed |
spelling | pubmed-67246022019-09-06 Mitochondrial carrier protein overloading and misfolding induce aggresomes and proteostatic adaptations in the cytosol Liu, Yaxin Wang, Xiaowen Coyne, Liam P. Yang, Yuan Qi, Yue Middleton, Frank A. Chen, Xin Jie Mol Biol Cell Articles Previous studies in yeast showed that mitochondrial stressors not directly targeting the protein import machinery can cause mitochondrial precursor overaccumulation stress (mPOS) in the cytosol independent of bioenergetics. Here, we demonstrate mPOS and stress responses in human cells. We show that overloading of mitochondrial membrane carrier, but not matrix proteins, is sufficient to induce cytosolic aggresomes and apoptosis. The aggresomes appear to triage unimported mitochondrial proteins. Interestingly, expression of highly unstable mutant variants of the mitochondrial carrier protein, Ant1, also induces aggresomes despite a greater than 20-fold reduction in protein level compared to wild type. Thus, overloading of the protein import machinery, rather than protein accumulation, is critical for aggresome induction. The data suggest that the import of mitochondrial proteins is saturable and that the cytosol is limited in degrading unimported mitochondrial proteins. In addition, we found that EGR1, eEF1a, and ubiquitin C are up-regulated by Ant1 overloading. These proteins are known to promote autophagy, protein targeting to aggresomes, and the processing of protein aggregates, respectively. Finally, we found that overexpression of the misfolded variants of Ant1 induces additional cytosolic responses including proteasomal activation. In summary, our work captured a profound effect of unimported mitochondrial proteins on cytosolic proteostasis and revealed multiple anti-mPOS mechanisms in human cells. The American Society for Cell Biology 2019-05-15 /pmc/articles/PMC6724602/ /pubmed/30893019 http://dx.doi.org/10.1091/mbc.E19-01-0046 Text en © 2019 Liu, Wang, Coyne, et al. “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society for Cell Biology. http://creativecommons.org/licenses/by-nc-sa/3.0 This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License. |
spellingShingle | Articles Liu, Yaxin Wang, Xiaowen Coyne, Liam P. Yang, Yuan Qi, Yue Middleton, Frank A. Chen, Xin Jie Mitochondrial carrier protein overloading and misfolding induce aggresomes and proteostatic adaptations in the cytosol |
title | Mitochondrial carrier protein overloading and misfolding induce aggresomes and proteostatic adaptations in the cytosol |
title_full | Mitochondrial carrier protein overloading and misfolding induce aggresomes and proteostatic adaptations in the cytosol |
title_fullStr | Mitochondrial carrier protein overloading and misfolding induce aggresomes and proteostatic adaptations in the cytosol |
title_full_unstemmed | Mitochondrial carrier protein overloading and misfolding induce aggresomes and proteostatic adaptations in the cytosol |
title_short | Mitochondrial carrier protein overloading and misfolding induce aggresomes and proteostatic adaptations in the cytosol |
title_sort | mitochondrial carrier protein overloading and misfolding induce aggresomes and proteostatic adaptations in the cytosol |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6724602/ https://www.ncbi.nlm.nih.gov/pubmed/30893019 http://dx.doi.org/10.1091/mbc.E19-01-0046 |
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