Article

Enhancing mitochondrial proteostasis reduces amyloid-β proteotoxicity

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Abstract

Alzheimer’s disease is a common and devastating disease characterized by aggregation of the amyloid-β peptide. However, we know relatively little about the underlying molecular mechanisms or how to treat patients with Alzheimer’s disease. Here we provide bioinformatic and experimental evidence of a conserved mitochondrial stress response signature present in diseases involving amyloid-β proteotoxicity in human, mouse and Caenorhabditis elegans that involves the mitochondrial unfolded protein response and mitophagy pathways. Using a worm model of amyloid-β proteotoxicity, GMC101, we recapitulated mitochondrial features and confirmed that the induction of this mitochondrial stress response was essential for the maintenance of mitochondrial proteostasis and health. Notably, increasing mitochondrial proteostasis by pharmacologically and genetically targeting mitochondrial translation and mitophagy increases the fitness and lifespan of GMC101 worms and reduces amyloid aggregation in cells, worms and in transgenic mouse models of Alzheimer’s disease. Our data support the relevance of enhancing mitochondrial proteostasis to delay amyloid-β proteotoxic diseases, such as Alzheimer’s disease.

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Acknowledgements

We thank P. Gönczy and M. Pierron (EPFL) for sharing reagents, the Caenorhabditis Genetics Center, which is funded by NIH Office of Research Infrastructure Programs (P40 OD010440), for providing worm strains. V.S. is supported by the ‘EPFL Fellows’ program co-funded by the Marie Skłodowska-Curie, Horizon 2020 Grant agreement (665667). D.D. is supported by a fellowship funded by Associazione Italiana per la Ricerca sul Cancro (AIRC). S.E.C. is supported by NIH grants (P01AG014449, R21AG053581 and P30 AG053760). The research of J.A. is supported by the EPFL, NIH (R01AG043930), Systems X (SySX.ch 2013/153), Velux Stiftung (1019), the Jebsen Foundation and the Swiss National Science Foundation (31003A-140780).

Author information

Author notes

    • Mario Romani
    •  & Laurent Mouchiroud

    These authors contributed equally to this work.

Affiliations

  1. Laboratory for Integrative and Systems Physiology, Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland

    • Vincenzo Sorrentino
    • , Mario Romani
    • , Laurent Mouchiroud
    • , Hongbo Zhang
    • , Davide D’ Amico
    • , Norman Moullan
    • , Francesca Potenza
    • , Solène Rietsch
    •  & Johan Auwerx
  2. Department of Translational Science and Molecular Medicine, Department of Family Medicine, Michigan State University, Grand Rapids, Michigan 49503, USA

    • John S. Beck
    •  & Scott E. Counts
  3. Proteomics Core Facility, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland

    • Adrien W. Schmid

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Contributions

V.S. and J.A. conceived and designed the project. V.S., L.M., M.R., J.S.B., H.Z., D.D., F.P., N.M., A.W.S., S.R. and S.E.C. performed the experiments. V.S., M.R. and L.M. independently replicated worm experiments in Figs 2, 3, 4. V.S., L.M. and J.A. wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Johan Auwerx.

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

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    Supplementary Information

    This file contains Supplementary Tables 1-13, Supplementary Text and Supplementary Figure 1, the uncropped western blots

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    Life Sciences Reporting Summary

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