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Cytosolic aggregation of mitochondrial proteins disrupts cellular homeostasis by stimulating the aggregation of other proteins
Mitochondria are organelles with their own genomes, but they rely on the import of nuclear-encoded proteins that are translated by cytosolic ribosomes. Therefore, it is important to understand whether failures in the mitochondrial uptake of these nuclear-encoded proteins can cause proteotoxic stress...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8457837/ https://www.ncbi.nlm.nih.gov/pubmed/34292154 http://dx.doi.org/10.7554/eLife.65484 |
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author | Nowicka, Urszula Chroscicki, Piotr Stroobants, Karen Sladowska, Maria Turek, Michal Uszczynska-Ratajczak, Barbara Kundra, Rishika Goral, Tomasz Perni, Michele Dobson, Christopher M Vendruscolo, Michele Chacinska, Agnieszka |
author_facet | Nowicka, Urszula Chroscicki, Piotr Stroobants, Karen Sladowska, Maria Turek, Michal Uszczynska-Ratajczak, Barbara Kundra, Rishika Goral, Tomasz Perni, Michele Dobson, Christopher M Vendruscolo, Michele Chacinska, Agnieszka |
author_sort | Nowicka, Urszula |
collection | PubMed |
description | Mitochondria are organelles with their own genomes, but they rely on the import of nuclear-encoded proteins that are translated by cytosolic ribosomes. Therefore, it is important to understand whether failures in the mitochondrial uptake of these nuclear-encoded proteins can cause proteotoxic stress and identify response mechanisms that may counteract it. Here, we report that upon impairments in mitochondrial protein import, high-risk precursor and immature forms of mitochondrial proteins form aberrant deposits in the cytosol. These deposits then cause further cytosolic accumulation and consequently aggregation of other mitochondrial proteins and disease-related proteins, including α-synuclein and amyloid β. This aggregation triggers a cytosolic protein homeostasis imbalance that is accompanied by specific molecular chaperone responses at both the transcriptomic and protein levels. Altogether, our results provide evidence that mitochondrial dysfunction, specifically protein import defects, contributes to impairments in protein homeostasis, thus revealing a possible molecular mechanism by which mitochondria are involved in neurodegenerative diseases. |
format | Online Article Text |
id | pubmed-8457837 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-84578372021-09-24 Cytosolic aggregation of mitochondrial proteins disrupts cellular homeostasis by stimulating the aggregation of other proteins Nowicka, Urszula Chroscicki, Piotr Stroobants, Karen Sladowska, Maria Turek, Michal Uszczynska-Ratajczak, Barbara Kundra, Rishika Goral, Tomasz Perni, Michele Dobson, Christopher M Vendruscolo, Michele Chacinska, Agnieszka eLife Biochemistry and Chemical Biology Mitochondria are organelles with their own genomes, but they rely on the import of nuclear-encoded proteins that are translated by cytosolic ribosomes. Therefore, it is important to understand whether failures in the mitochondrial uptake of these nuclear-encoded proteins can cause proteotoxic stress and identify response mechanisms that may counteract it. Here, we report that upon impairments in mitochondrial protein import, high-risk precursor and immature forms of mitochondrial proteins form aberrant deposits in the cytosol. These deposits then cause further cytosolic accumulation and consequently aggregation of other mitochondrial proteins and disease-related proteins, including α-synuclein and amyloid β. This aggregation triggers a cytosolic protein homeostasis imbalance that is accompanied by specific molecular chaperone responses at both the transcriptomic and protein levels. Altogether, our results provide evidence that mitochondrial dysfunction, specifically protein import defects, contributes to impairments in protein homeostasis, thus revealing a possible molecular mechanism by which mitochondria are involved in neurodegenerative diseases. eLife Sciences Publications, Ltd 2021-07-20 /pmc/articles/PMC8457837/ /pubmed/34292154 http://dx.doi.org/10.7554/eLife.65484 Text en © 2021, Nowicka et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Biochemistry and Chemical Biology Nowicka, Urszula Chroscicki, Piotr Stroobants, Karen Sladowska, Maria Turek, Michal Uszczynska-Ratajczak, Barbara Kundra, Rishika Goral, Tomasz Perni, Michele Dobson, Christopher M Vendruscolo, Michele Chacinska, Agnieszka Cytosolic aggregation of mitochondrial proteins disrupts cellular homeostasis by stimulating the aggregation of other proteins |
title | Cytosolic aggregation of mitochondrial proteins disrupts cellular homeostasis by stimulating the aggregation of other proteins |
title_full | Cytosolic aggregation of mitochondrial proteins disrupts cellular homeostasis by stimulating the aggregation of other proteins |
title_fullStr | Cytosolic aggregation of mitochondrial proteins disrupts cellular homeostasis by stimulating the aggregation of other proteins |
title_full_unstemmed | Cytosolic aggregation of mitochondrial proteins disrupts cellular homeostasis by stimulating the aggregation of other proteins |
title_short | Cytosolic aggregation of mitochondrial proteins disrupts cellular homeostasis by stimulating the aggregation of other proteins |
title_sort | cytosolic aggregation of mitochondrial proteins disrupts cellular homeostasis by stimulating the aggregation of other proteins |
topic | Biochemistry and Chemical Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8457837/ https://www.ncbi.nlm.nih.gov/pubmed/34292154 http://dx.doi.org/10.7554/eLife.65484 |
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