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
-
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.
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
-
- 6,175
- views
-
- 818
- downloads
-
- 72
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
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)
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
Further reading
-
- Biochemistry and Chemical Biology
- Genetics and Genomics
Deep Mutational Scanning (DMS) is an emerging method to systematically test the functional consequences of thousands of sequence changes to a protein target in a single experiment. Because of its utility in interpreting both human variant effects and protein structure-function relationships, it holds substantial promise to improve drug discovery and clinical development. However, applications in this domain require improved experimental and analytical methods. To address this need, we report novel DMS methods to precisely and quantitatively interrogate disease-relevant mechanisms, protein-ligand interactions, and assess predicted response to drug treatment. Using these methods, we performed a DMS of the melanocortin-4 receptor (MC4R), a G-protein-coupled receptor (GPCR) implicated in obesity and an active target of drug development efforts. We assessed the effects of >6600 single amino acid substitutions on MC4R’s function across 18 distinct experimental conditions, resulting in >20 million unique measurements. From this, we identified variants that have unique effects on MC4R-mediated Gαs- and Gαq-signaling pathways, which could be used to design drugs that selectively bias MC4R’s activity. We also identified pathogenic variants that are likely amenable to a corrector therapy. Finally, we functionally characterized structural relationships that distinguish the binding of peptide versus small molecule ligands, which could guide compound optimization. Collectively, these results demonstrate that DMS is a powerful method to empower drug discovery and development.
-
- Biochemistry and Chemical Biology
Copper is an essential enzyme cofactor in bacteria, but excess copper is highly toxic. Bacteria can cope with copper stress by increasing copper resistance and initiating chemorepellent response. However, it remains unclear how bacteria coordinate chemotaxis and resistance to copper. By screening proteins that interacted with the chemotaxis kinase CheA, we identified a copper-binding repressor CsoR that interacted with CheA in Pseudomonas putida. CsoR interacted with the HPT (P1), Dimer (P3), and HATPase_c (P4) domains of CheA and inhibited CheA autophosphorylation, resulting in decreased chemotaxis. The copper-binding of CsoR weakened its interaction with CheA, which relieved the inhibition of chemotaxis by CsoR. In addition, CsoR bound to the promoter of copper-resistance genes to inhibit gene expression, and copper-binding released CsoR from the promoter, leading to increased gene expression and copper resistance. P. putida cells exhibited a chemorepellent response to copper in a CheA-dependent manner, and CsoR inhibited the chemorepellent response to copper. Besides, the CheA-CsoR interaction also existed in proteins from several other bacterial species. Our results revealed a mechanism by which bacteria coordinately regulated chemotaxis and resistance to copper by CsoR.
