1. Biochemistry and Chemical Biology
Download icon

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

Research Article
  • Cited 0
  • Views 972
  • Annotations
Cite this article as: eLife 2021;10:e65484 doi: 10.7554/eLife.65484

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

Publication history

  1. Received: December 4, 2020
  2. Accepted: July 19, 2021
  3. Accepted Manuscript published: July 20, 2021 (version 1)

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.

Metrics

  • 972
    Page views
  • 197
    Downloads
  • 0
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Further reading

    1. Biochemistry and Chemical Biology
    2. Cell Biology
    Jingxiang Li et al.
    Research Article Updated

    Autophagy acts as a pivotal innate immune response against infection. Some virulence effectors subvert the host autophagic machinery to escape the surveillance of autophagy. The mechanism by which pathogens interact with host autophagy remains mostly unclear. However, traditional strategies often have difficulty identifying host proteins that interact with effectors due to the weak, dynamic, and transient nature of these interactions. Here, we found that Enteropathogenic Escherichia coli (EPEC) regulates autophagosome formation in host cells dependent on effector NleE. The 26S Proteasome Regulatory Subunit 10 (PSMD10) was identified as a direct interaction partner of NleE in living cells by employing genetically incorporated crosslinkers. Pairwise chemical crosslinking revealed that NleE interacts with the N-terminus of PSMD10. We demonstrated that PSMD10 homodimerization is necessary for its interaction with ATG7 and promotion of autophagy, but not necessary for PSMD10 interaction with ATG12. Therefore, NleE-mediated PSMD10 in monomeric state attenuates host autophagosome formation. Our study reveals the mechanism through which EPEC attenuates host autophagy activity.

    1. Biochemistry and Chemical Biology
    2. Structural Biology and Molecular Biophysics
    Bence Hajdusits et al.
    Research Article

    In Gram-positive bacteria, the McsB protein arginine kinase is central to protein quality control, labelling aberrant molecules for degradation by the ClpCP protease. Despite its importance for stress response and pathogenicity, it is still elusive how the bacterial degradation labelling is regulated. Here, we delineate the mechanism how McsB targets aberrant proteins during stress conditions. Structural data reveal a self-compartmentalized kinase, in which the active sites are sequestered in a molecular cage. The 'closed' octamer interconverts with other oligomers in a phosphorylation-dependent manner and, contrary to these 'open' forms, preferentially labels unfolded proteins. In vivo data show that heat-shock triggers accumulation of higher-order oligomers, of which the octameric McsB is essential for surviving stress situations. The interconversion of open and closed oligomers represents a distinct regulatory mechanism of a degradation labeler, allowing the McsB kinase to adapt its potentially dangerous enzyme function to the needs of the bacterial cell.