Enhancing mitochondrial proteostasis reduces amyloid-β proteotoxicity.
- Sorrentino V Laboratory for Integrative and Systems Physiology, Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland.
- Romani M Laboratory for Integrative and Systems Physiology, Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland.
- Mouchiroud L Laboratory for Integrative and Systems Physiology, Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland.
- Beck JS Department of Translational Science and Molecular Medicine, Department of Family Medicine, Michigan State University, Grand Rapids, Michigan 49503, USA.
- Zhang H Laboratory for Integrative and Systems Physiology, Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland.
- D'Amico D Laboratory for Integrative and Systems Physiology, Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland.
- Moullan N Laboratory for Integrative and Systems Physiology, Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland.
- Potenza F Laboratory for Integrative and Systems Physiology, Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland.
- Schmid AW Proteomics Core Facility, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland.
- Rietsch S Laboratory for Integrative and Systems Physiology, Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland.
- Counts SE Department of Translational Science and Molecular Medicine, Department of Family Medicine, Michigan State University, Grand Rapids, Michigan 49503, USA.
- Auwerx J Laboratory for Integrative and Systems Physiology, Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland.
- 2017-12-07
Published in:
- Nature. - 2017
Alzheimer Disease
Amyloid beta-Peptides
Animals
Caenorhabditis elegans
Disease Models, Animal
Homeostasis
Humans
Male
Memory
Mice
Mice, Transgenic
Mitochondria
Mitophagy
NAD
Niacinamide
Oxidative Phosphorylation
Protein Aggregation, Pathological
Protein Biosynthesis
Proteostasis
Unfolded Protein Response
English
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.
- Language
-
- English
- Open access status
- green
- Identifiers
-
- DOI 10.1038/nature25143
- PMID 29211722
- Persistent URL
- https://sonar.ch/global/documents/204489
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