1. Biochemistry and Chemical Biology

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

  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  Is a corresponding author
  1. University of Warsaw, Poland
  2. University of Cambridge, United Kingdom
https://doi.org/10.7554/eLife.65484
Share this article
Cite this article
  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
  2. Download BibTeX
  3. Download .RIS

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. 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.

Metrics

  • 3,752
    Page views
  • 552
    Downloads
  • 6
    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)

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

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

  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

Categories and tags

Research organisms

Further reading

    1. Biochemistry and Chemical Biology

    Hypertrophic cardiomyopathy mutations in the pliant and light chain-binding regions of the lever arm of human β-cardiac myosin have divergent effects on myosin function

    Makenna M Morck et al.
    Research Article

    Mutations in the lever arm of β-cardiac myosin are a frequent cause of hypertrophic cardiomyopathy, a disease characterized by hypercontractility and eventual hypertrophy of the left ventricle. Here, we studied five such mutations: three in the pliant region of the lever arm (D778V, L781P, and S782N) and two in the light chain-binding region (A797T and F834L). We investigated their effects on both motor function and myosin subfragment 2 (S2) tail-based autoinhibition. The pliant region mutations had varying effects on the motor function of a myosin construct lacking the S2 tail: overall, D778V increased power output, L781P reduced power output, and S782N had little effect on power output, while all three reduced the external force sensitivity of the actin detachment rate. With a myosin containing the motor domain and the proximal S2 tail, the pliant region mutations also attenuated autoinhibition in the presence of filamentous actin but had no impact in the absence of actin. By contrast, the light chain-binding region mutations had little effect on motor activity but produced marked reductions in autoinhibition in both the presence and absence of actin. Thus, mutations in the lever arm of β-cardiac myosin have divergent allosteric effects on myosin function, depending on whether they are in the pliant or light chain-binding regions.

    1. Biochemistry and Chemical Biology

    DIP2 is a unique regulator of diacylglycerol lipid homeostasis in eukaryotes

    Sudipta Mondal et al.
    Research Article

    Chain-length specific subsets of diacylglycerol (DAG) lipids are proposed to regulate differential physiological responses ranging from signal transduction to modulation of the membrane properties. However, the mechanism or molecular players regulating the subsets of DAG species remains unknown. Here, we uncover the role of a conserved eukaryotic protein family, DISCO-interacting protein 2 (DIP2) as a homeostatic regulator of a chemically distinct subset of DAGs using yeast, fly and mouse models. Genetic and chemical screens along with lipidomics analysis in yeast reveal that DIP2 prevents the toxic accumulation of specific DAGs in the logarithmic growth phase, which otherwise leads to endoplasmic reticulum stress. We also show that the fatty acyl-AMP ligase-like domains of DIP2 are essential for the redirection of the flux of DAG subspecies to storage lipid, triacylglycerols. DIP2 is associated with vacuoles through mitochondria-vacuole contact sites and such modulation of selective DAG abundance by DIP2 is found to be crucial for optimal vacuole membrane fusion and consequently osmoadaptation in yeast. Thus, the study illuminates an unprecedented DAG metabolism route and provides new insights on how cell fine-tunes DAG subspecies for cellular homeostasis and environmental adaptation.

    1. Biochemistry and Chemical Biology
    2. Microbiology and Infectious Disease

    Antibacterial potency of Type VI amidase effector toxins is dependent on substrate topology and cellular context

    Atanas Radkov et al.
    Research Article

    Members of the bacterial T6SS amidase effector (Tae) superfamily of toxins are delivered between competing bacteria to degrade cell wall peptidoglycan. Although Taes share a common substrate, they exhibit distinct antimicrobial potency across different competitor species. To investigate the molecular basis governing these differences, we quantitatively defined the functional determinants of Tae1 from Pseudomonas aeruginosa PAO1 using a combination of nuclear magnetic resonance (NMR) and a high-throughput in vivo genetic approach called deep mutational scanning (DMS). As expected, combined analyses confirmed the role of critical residues near the Tae1 catalytic center. Unexpectedly, DMS revealed substantial contributions to enzymatic activity from a much larger, ring-like functional hot spot extending around the entire circumference of the enzyme. Comparative DMS across distinct growth conditions highlighted how functional contribution of different surfaces is highly context-dependent, varying alongside composition of targeted cell walls. These observations suggest that Tae1 engages with the intact cell wall network through a more distributed three-dimensional interaction interface than previously appreciated, providing an explanation for observed differences in antimicrobial potency across divergent Gram-negative competitors. Further binding studies of several Tae1 variants with their cognate immunity protein demonstrate that requirements to maintain protection from Tae activity may be a significant constraint on the mutational landscape of tae1 toxicity in the wild. In total, our work reveals that Tae diversification has likely been shaped by multiple independent pressures to maintain interactions with binding partners that vary across bacterial species and conditions.