Cytosolic aggregation of mitochondrial proteins disrupts cellular homeostasis by stimulating the aggregation of other proteins

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

The following data sets were generated

Article and author information

Author details

  1. Urszula Nowicka

    Centre of New Technologies, University of Warsaw, Warsaw, Poland
    Competing interests
    No competing interests declared.
  2. Piotr Chroscicki

    Centre of New Technologies, University of Warsaw, Warsaw, Poland
    Competing interests
    No competing interests declared.
  3. Karen Stroobants

    Department of Chemistry, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    No competing interests declared.
  4. Maria Sladowska

    Centre of New Technologies, University of Warsaw, Warsaw, Poland
    Competing interests
    No competing interests declared.
  5. Michal Turek

    Centre of New Technologies, University of Warsaw, Warsaw, Poland
    Competing interests
    No competing interests declared.
  6. Barbara Uszczynska-Ratajczak

    Centre of New Technologies, University of Warsaw, Warsaw, Poland
    Competing interests
    No competing interests declared.
  7. Rishika Kundra

    Department of Chemistry, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    No competing interests declared.
  8. Tomasz Goral

    Centre of New Technologies, University of Warsaw, Warsaw, Poland
    Competing interests
    No competing interests declared.
  9. Michele Perni

    Chemistry, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7593-8376
  10. Christopher M Dobson

    Department of Chemistry, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    No competing interests declared.
  11. Michele Vendruscolo

    Department of Chemistry, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3616-1610
  12. Agnieszka Chacinska

    Centre of New Technologies, University of Warsaw, Warsaw, Poland
    For correspondence
    a.chacinska@imol.institute
    Competing interests
    Agnieszka Chacinska, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2832-2568

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

  1. Maya Schuldiner, Weizmann Institute, Israel

Version history

  1. Received: December 4, 2020
  2. Preprint posted: May 2, 2021 (view preprint)
  3. Accepted: July 19, 2021
  4. Accepted Manuscript published: July 20, 2021 (version 1)
  5. 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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  1. Urszula Nowicka
  2. Piotr Chroscicki
  3. Karen Stroobants
  4. Maria Sladowska
  5. Michal Turek
  6. Barbara Uszczynska-Ratajczak
  7. Rishika Kundra
  8. Tomasz Goral
  9. Michele Perni
  10. Christopher M Dobson
  11. Michele Vendruscolo
  12. Agnieszka Chacinska
(2021)
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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https://doi.org/10.7554/eLife.65484

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