Loss of hepatic chaperone‐mediated autophagy accelerates proteostasis failure in aging |
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| Authors: | Jaime L Schneider Joan Villarroya Antonio Diaz‐Carretero Bindi Patel Aleksandra M Urbanska Mia M Thi Francesc Villarroya Laura Santambrogio Ana Maria Cuervo |
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| Affiliation: | 1. Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY, USA;2. Institute for Aging Studies, Albert Einstein College of Medicine, Bronx, NY, USA;3. Hospital de la Santa Creu i Sant Pau, Barcelona, Spain;4. Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, USA;5. Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY, USA;6. Department of Biochemistry and Molecular Biology, University of Barcelona, and CIBER Fisiopatologia Obesidad y Nutrición, Barcelona, Spain |
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| Abstract: | Chaperone‐mediated autophagy (CMA), a cellular process that contributes to protein quality control through targeting of a subset of cytosolic proteins to lysosomes for degradation, undergoes a functional decline with age. We have used a mouse model with liver‐specific defective CMA to identify changes in proteostasis attributable to reduced CMA activity in this organ with age. We have found that other proteolytic systems compensate for CMA loss in young mice which helps to preserve proteostasis. However, these compensatory responses are not sufficient for protection against proteotoxicity induced by stress (oxidative stress, lipid challenges) or associated with aging. Livers from old mice with CMA blockage exhibit altered protein homeostasis, enhanced susceptibility to oxidative stress and hepatic dysfunction manifested by a diminished ability to metabolize drugs, and a worsening of the metabolic dysregulation identified in young mice. Our study reveals that while the regulatory function of CMA cannot be compensated for in young organisms, its contribution to protein homeostasis can be handled by other proteolytic systems. However, the decline in the compensatory ability identified with age explains the more severe consequences of CMA impairment in older organisms and the contribution of CMA malfunction to the gradual decline in proteostasis and stress resistance observed during aging. |
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| Keywords: | autophagy lysosomal protein degradation macroautophagy oxidative stress proteotoxicity protein aggregation ubiquitin‐proteasome system |
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