Cytosolic aggregation of mitochondrial proteins disrupts cellular homeostasis by stimulating the aggregation of other proteins
- University of Warsaw, Poland
- University of Cambridge, United Kingdom
Abstract
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.
Data availability
Sequencing data have been deposited in GEO under accession codes GSE147284
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Cytosolic aggregation of mitochondrial proteins enhances degeneration of cellular homeostasisNCBI Gene Expression Omnibus, GSE147284.
Article and author information
Author details
Michele Vendruscolo
Agnieszka Chacinska
Funding
Centre for Misfolding Diseases
- Michele Vendruscolo
National Science Centre (2015/18/A/NZ1/00025)
- Agnieszka Chacinska
Ministerial funds for science (Ideas Plus,000263)
- Agnieszka Chacinska
Foundation of Polish Science and German Research Foundation (Copernicus Award)
- Agnieszka Chacinska
Foundation for Polish Science co-financed by the European Union under the Eropean Regional Development Fund (Homing,POIR.04.04.00-00-3FE4/17)
- Urszula Nowicka
European Union's Horizon 2020, Marie Sklodowska-Curie grant agreement No 665778 (POLONEZ,2016/23/P/NZ3/03730)
- Barbara Uszczynska-Ratajczak
European Union's Horizon 2020, Marie Sklodowska-Curie grant agreement No 665778 (POLONEZ,2016/21JPJNZ3/03891)
- Michal Turek
EMBO (Short-term fellowship,7124)
- Maria Sladowska
William B. Harrison Foundation
- Michele Vendruscolo
Foundation for Polish Science co-financed by the European Union under the Eropean Regional Development Fund (International Research Agendas programme, Regenerative Mechanisms for Health, MAB/2017/2)
- Agnieszka Chacinska
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Maya Schuldiner, Weizmann Institute, Israel
Publication history
- Received: December 4, 2020
- Preprint posted: May 2, 2021 (view preprint)
- Accepted: July 19, 2021
- Accepted Manuscript published: July 20, 2021 (version 1)
- Version of Record published: September 22, 2021 (version 2)
Copyright
© 2021, Nowicka et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Cytosolic aggregation of mitochondrial proteins disrupts cellular homeostasis by stimulating the aggregation of other proteins
eLife 10:e65484.
https://doi.org/10.7554/eLife.65484
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