This proposal focuses on chaperone-mediated autophagy (CMA), a catabolic pathway that mediates the selective degradation of cytosolic proteins in lysosomes. CMA contributes to the maintenance of cellular homeostasis by participating in cellular quality control. We have previously found that CMA activity decreases with age and that restoration of proper CMA activity in livers of old rodents prevents organ deterioration and preserves organ function. We propose that failure of CMA contributes to the functional decline characteristic of old organisms and aggravates the course of age-related diseases. The overall goal of this proposal is 1) to identify the causes behind the functional failure of CMA with age, 2) to understand the consequences of the decrease in CMA activity with age in different organs and 3) to explore alternative interventions to the genetic manipulation to enhance CMA activity in aging organisms. With this purpose, during the next period of funding we intend to: 1) determine the contribution of lysosomal chaperones and co-chaperones to the lysosomal internalization of substrate proteins through the CMA translocation complex;2) elucidate the contribution of CMA to the regulation of cellular lipid metabolism through maintenance of endoplasmic reticulum and lipid droplet homeostasis and 3) analyze the systemic and organ-specific consequences of the decrease in CMA activity with age in relation to the function of this pathway in cellular quality control and in the regulation of the metabolic balance. Significance: This study will elucidate how functional decline of CMA contributes to aging and could help identifying new approaches to correct defective CMA in old organisms and prevent the alterations in cellular and organ homeostasis characteristics of aging
Cellular and organ deterioration in old organisms results, at least in part, from a failure of the systems responsible for the maintenance of cellular quality control. Malfunctioning of these surveillance systems also underlies the basis of severe diseases associated with aging such as neurodegeneration, metabolic disorders or muscle weakness. This proposal focuses on one of the mechanisms that contribute to cellular cleaning whose activity is severely compromised with age. Understanding the reasons for the failure of this system in old organisms and the impact that the decline in its activity has on different aged organs should aid in the development of interventions based on the modulation of this system to slow down the aging process and to delay the onset or reduce the severity of different 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 |
| Gong, Zhenwei; Tasset, Inmaculada; Diaz, Antonio et al. (2018) Humanin is an endogenous activator of chaperone-mediated autophagy. J Cell Biol 217:635-647 |
| Esteban-MartÃnez, Lorena; Sierra-Filardi, Elena; McGreal, Rebecca S et al. (2017) Programmed mitophagy is essential for the glycolytic switch during cell differentiation. EMBO J 36:1688-1706 |
| Zhang, Jinzhong; Johnson, Jennifer L; He, Jing et al. (2017) Cystinosin, the small GTPase Rab11, and the Rab7 effector RILP regulate intracellular trafficking of the chaperone-mediated autophagy receptor LAMP2A. J Biol Chem 292:10328-10346 |
| Gomes, Luciana R; Menck, Carlos F M; Cuervo, Ana Maria (2017) Chaperone-mediated autophagy prevents cellular transformation by regulating MYC proteasomal degradation. Autophagy 13:928-940 |
| Galluzzi, Lorenzo; Baehrecke, Eric H; Ballabio, Andrea et al. (2017) Molecular definitions of autophagy and related processes. EMBO J 36:1811-1836 |
| Klionsky, Daniel J (see original citation for additional authors) (2016) Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 12:1-222 |
| Kaushik, Susmita; Cuervo, Ana Maria (2016) AMPK-dependent phosphorylation of lipid droplet protein PLIN2 triggers its degradation by CMA. Autophagy 12:432-8 |
| Pampliega, Olatz; Cuervo, Ana Maria (2016) Autophagy and primary cilia: dual interplay. Curr Opin Cell Biol 39:1-7 |
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