Sorrentino V Romani M Mouchiroud L Beck JS Zhang H D'Amico D Moullan N Potenza F Schmid AW Rietsch S Counts SE Auwerx J 2017 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. application/pdf https://sonar.ch/global/documents/204489 eng info:eu-repo/semantics/altIdentifier/doi/10.1038/nature25143 info:eu-repo/semantics/altIdentifier/pmid/29211722 info:eu-repo/semantics/openAccess 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 Enhancing mitochondrial proteostasis reduces amyloid-β proteotoxicity. http://purl.org/coar/resource_type/c_6501