Enhancing mitochondrial proteostasis reduces amyloid-β proteotoxicity Vincenzo Sorrentino1, Mario Romani1, Laurent Mouchiroud1, John S. Beck2, Hongbo Zhang1, Davide D'Amico1, Norman Moullan1, Francesca Potenza1, Adrien W. Schmid3, Solène Rietsch1, Scott E. Counts2, Johan Auwerx1 1Laboratory for Integrative and Systems Physiology, Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland; 2Department of Translational Science and Molecular Medicine, Department of Family Medicine, Michigan State University, Grand Rapids, MI 49503, USA; 3Proteomics Core Facility, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland
Alzheimer's disease (AD) is a common and devastating disease characterized by the aggregation of amyloid-β peptide (Aβ), yet we know relatively little about the underlying molecular mechanisms or how to treat AD patients. Here, we provide bioinformatic and experimental evidence of a conserved mitochondrial stress response signature present in Aβ proteotoxic diseases in human, mouse and C. elegans, and which involves the UPRmt and mitophagy pathways. Using the worm model of Aβ proteotoxicity, GMC101, we recapitulated mitochondrial features and confirmed the induction of this mitochondrial stress response as key to maintain mitochondrial proteostasis and health. Importantly, boosting mitochondrial proteostasis by pharmacologically and genetically targeting mitochondrial translation and mitophagy increases fitness and lifespan of GMC101 worms and reduces amyloid aggregation in cells, worms, and in AD transgenic mice. Our data support the relevance of enhancing mitochondrial proteostasis to delay Aβ proteotoxic diseases, such as AD.
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