All intracellular components are subjected to constant synthesis and degradation which guarantees their continuous renewal. This application focuses on a cellular pathway, known as chaperone-mediated autophagy (CMA), responsible for the selective removal of cytosolic proteins in lysosomes. We have previously identified that the activity of this pathway decreases with age and proposed that declined CMA activity could contribute to the intracellular accumulation of altered proteins characteristic of old organisms. The long-term goal of our study is to understand the cause(s) and consequences of the decrease in CMA activity with age and to restore normal CMA activity in old organisms and analyze the possible beneficial effects of this intervention. We will use in vitro systems with isolated lysosomes and in vivo mouse models with altered or improved CMA activity to: 1) determine the changes in the lysosomal compartment responsible for the observed instability of the receptor for CMA in old organisms; 2) identify the signaling mechanisms that regulate CMA activity; 3) analyze the systemic consequences of changes in CMA activity with age and the possible beneficial effect of multi-organ preservation of normal CMA activity until advanced ages in life-span and incidence of age-related diseases. The studies proposed in this project should provide the basis for new approaches to restore CMA in old organisms and in pathological conditions with altered activity of this catabolic pathway.
TO PUBLIC HEALTH: The gradual deterioration of the cellular quality control systems is in part responsible for the loss of function and the high incidence of disease as individuals age. Alteration of these systems is on the basis of detrimental metabolic and neurodegenerative disorders, highly prevalent in the aging population, such as diabetes or Alzheimer's disease. Understanding the contribution of alterations in CMA to the poor handling of altered proteins in old organisms is essential for any future efforts to improve functional performance in elders and to delay the onset of age-related diseases. ? ? ?
| Tekirdag, Kumsal; Cuervo, Ana Maria (2018) Chaperone-mediated autophagy and endosomal microautophagy: Joint by a chaperone. J Biol Chem 293:5414-5424 |
| Kaushik, Susmita; Cuervo, Ana Maria (2018) The coming of age of chaperone-mediated autophagy. Nat Rev Mol Cell Biol 19:365-381 |
| Bejarano, Eloy; Murray, John W; Wang, Xintao et al. (2018) Defective recruitment of motor proteins to autophagic compartments contributes to autophagic failure in aging. Aging Cell :e12777 |
| Gong, Zhenwei; Tasset, Inmaculada; Diaz, Antonio et al. (2018) Humanin is an endogenous activator of chaperone-mediated autophagy. J Cell Biol 217:635-647 |
| Kaushik, Susmita; Cuervo, Ana Maria (2016) AMPK-dependent phosphorylation of lipid droplet protein PLIN2 triggers its degradation by CMA. Autophagy 12:432-8 |
| Tasset, Inmaculada; Cuervo, Ana Maria (2016) Role of chaperone-mediated autophagy in metabolism. FEBS J 283:2403-13 |
| Madrigal-Matute, Julio; Cuervo, Ana Maria (2016) Regulation of Liver Metabolism by Autophagy. Gastroenterology 150:328-39 |
| Schneider, Jaime L; Villarroya, Joan; Diaz-Carretero, Antonio et al. (2015) Loss of hepatic chaperone-mediated autophagy accelerates proteostasis failure in aging. Aging Cell 14:249-64 |
| Park, Caroline; Suh, Yousin; Cuervo, Ana Maria (2015) Regulated degradation of Chk1 by chaperone-mediated autophagy in response to DNA damage. Nat Commun 6:6823 |
| Arias, Esperanza; Koga, Hiroshi; Diaz, Antonio et al. (2015) Lysosomal mTORC2/PHLPP1/Akt Regulate Chaperone-Mediated Autophagy. Mol Cell 59:270-84 |
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