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Garbage in, all sorts out Until recently, autophagy, or cellular self-digestion, was thought of primarily as part of the cell's garbage disposal system. Now it is know to be involved in cellular protein and organelle degradation during development as well as during adaptations to changing environmental conditions. Many intriguing questions remain to be answered about this process. For example, how can this one pathway be involved in cytoprotection as well as cell death? What is the connection between autophagy and human disease or ageing? In a review, Mizushima et al . consider recent progress in the field. Autophagy, or cellular self-digestion, is a cellular pathway involved in protein and organelle degradation, with an astonishing number of connections to human disease and physiology. For example, autophagic dysfunction is associated with cancer, neurodegeneration, microbial infection and ageing. Paradoxically, although autophagy is primarily a protective process for the cell, it can also play a role in cell death. Understanding autophagy may ultimately allow scientists and clinicians to harness this process for the purpose of improving human health.

Chaperone-mediated autophagy (CMA) was the first studied process that indicated that degradation of intracellular components by the lysosome can be selective — a concept that is now well accepted for other forms of autophagy. Lysosomes can degrade cellular cytosol in a nonspecific manner but can also discriminate what to target for degradation with the involvement of a degradation tag, a chaperone and a sophisticated mechanism to make the selected proteins cross the lysosomal membrane through a dedicated translocation complex. Recent studies modulating CMA activity in vivo using transgenic mouse models have demonstrated that selectivity confers on CMA the ability to participate in the regulation of multiple cellular functions. Timely degradation of specific cellular proteins by CMA modulates, for example, glucose and lipid metabolism, DNA repair, cellular reprograming and the cellular response to stress. These findings expand the physiological relevance of CMA beyond its originally identified role in protein quality control and reveal that CMA failure with age may aggravate diseases, such as ageing-associated neurodegeneration and cancer.

Chaperone-mediated autophagy (CMA) selectively degrades a subset of cytosolic proteins in lysosomes. A potent physiological activator of CMA is nutrient deprivation, a condition in which intracellular triglyceride stores or lipid droplets (LDs) also undergo hydrolysis (lipolysis) to generate free fatty acids for energetic purposes. Here we report that the LD-associated proteins perilipin 2 (PLIN2) and perilipin 3 (PLIN3) are CMA substrates and their degradation through CMA precedes lipolysis. In vivo studies revealed that CMA degradation of PLIN2 and PLIN3 was enhanced during starvation, concurrent with elevated levels of cytosolic adipose triglyceride lipase (ATGL) and macroautophagy proteins on LDs. CMA blockage both in cultured cells and mouse liver or expression of CMA-resistant PLINs leads to reduced association of ATGL and macrolipophagy-related proteins with LDs and the subsequent decrease in lipid oxidation and accumulation of LDs. We propose a role for CMA in LD biology and in the maintenance of lipid homeostasis. Cuervo and colleagues find that perilipin proteins associated with lipid droplets are degraded by chaperone-mediated autophagy to facilitate recruitment of the lipolytic machinery to lipid droplets.

This review focuses on chaperone-mediated autophagy （CMA）, one of the proteolytic systems that contributes to degradation of intracellular proteins in lysosomes. CMA substrate proteins are selectively targeted to lysosomes and translocated into the lysosomal lumen through the coordinated action of chaperones located at both sides of the membrane and a dedicated protein translocation complex. The selectivity of CMA permits timed degradation of spe- cific proteins with regulatory purposes supporting a modulatory role for CMA in enzymatic metabolic processes and subsets of the cellular transcriptional program. In addition, CMA contributes to cellular quality control through the removal of damaged or malfunctioning proteins. Here, we describe recent advances in the understanding of the molecular dynamics, regulation and physiology of CMA, and discuss the evidence in support of the contribution of CMA dysfunction to severe human disorders such as neurodegeneration and cancer.

Induced pluripotent stem cells (iPSC) offer an unprecedented opportunity to model human disease in relevant cell types, but it is unclear whether they could successfully model age‐related diseases such as Parkinson's disease (PD). Here, we generated iPSC lines from seven patients with idiopathic PD (ID‐PD), four patients with familial PD associated to the G2019S mutation in the Leucine‐Rich Repeat Kinase 2 ( LRRK2 ) gene (LRRK2‐PD) and four age‐ and sex‐matched healthy individuals (Ctrl). Over long‐time culture, dopaminergic neurons (DAn) differentiated from either ID‐PD‐ or LRRK2‐PD‐iPSC showed morphological alterations, including reduced numbers of neurites and neurite arborization, as well as accumulation of autophagic vacuoles, which were not evident in DAn differentiated from Ctrl‐iPSC. Further induction of autophagy and/or inhibition of lysosomal proteolysis greatly exacerbated the DAn morphological alterations, indicating autophagic compromise in DAn from ID‐PD‐ and LRRK2‐PD‐iPSC, which we demonstrate occurs at the level of autophagosome clearance. Our study provides an iPSC‐based in vitro model that captures the patients' genetic complexity and allows investigation of the pathogenesis of both sporadic and familial PD cases in a disease‐relevant cell type.

Cells rely on surveillance systems such as autophagy to handle protein alterations and organelle damage. Dysfunctional autophagy, an evolutionarily conserved cellular mechanism for degradation of intracellular components in lysosomes, frequently leads to neurodegeneration. The neuroprotective effect of autophagy stems from its ability to eliminate pathogenic forms of proteins such as α-synuclein or tau. However, the same pathogenic proteins often affect different types and steps of the autophagic process. Furthermore, genetic studies have shown that some proteins related to neurodegeneration, such as huntingtin, participate in autophagy as one of their physiological functions. This complex interplay between autophagy and neurodegeneration suggests that targeting autophagy as a whole might have limited applicability in neurodegenerative diseases, and that future efforts should focus instead on targeting specific types and steps of the autophagic process. This change of strategy in the modulation of autophagy might hold promise for future disease-modifying therapies for patients with neurodegenerative disorders.

Chaperone-mediated autophagy (CMA), a mechanism for the lysosomal degradation of proteins, declines in aging cells. Using transgenic mice in which such a decline does not occur in the liver, the authors found that preserving CMA leads to reduced accumulation of damaged proteins and improved organ function in aged mice ( pages 909–910 ). Chaperone-mediated autophagy (CMA), a selective mechanism for degradation of cytosolic proteins in lysosomes, contributes to the removal of altered proteins as part of the cellular quality-control systems 1 , 2 . We have previously found that CMA activity declines in aged organisms and have proposed that this failure in cellular clearance could contribute to the accumulation of altered proteins, the abnormal cellular homeostasis and, eventually, the functional loss characteristic of aged organisms. To determine whether these negative features of aging can be prevented by maintaining efficient autophagic activity until late in life, in this work we have corrected the CMA defect in aged rodents. We have generated a double transgenic mouse model in which the amount of the lysosomal receptor for CMA, previously shown to decrease in abundance with age 3 , can be modulated. We have analyzed in this model the consequences of preventing the age-dependent decrease in receptor abundance in aged rodents at the cellular and organ levels. We show here that CMA activity is maintained until advanced ages if the decrease in the receptor abundance is prevented and that preservation of autophagic activity is associated with lower intracellular accumulation of damaged proteins, better ability to handle protein damage and improved organ function.

Chaperone-mediated autophagy (CMA) is activated in response to cellular stressors to prevent cellular proteotoxicity through selective degradation of altered proteins in lysosomes. Reduced CMA activity contributes to the decrease in proteome quality in disease and ageing. Here, we report that CMA is also upregulated in response to genotoxic insults and that declined CMA functionality leads to reduced cell survival and genomic instability. This role of CMA in genome quality control is exerted through regulated degradation of activated checkpoint kinase 1 (Chk1) by this pathway after the genotoxic insult. Nuclear accumulation of Chk1 in CMA-deficient cells compromises cell cycle progression and prolongs the time that DNA damage persists in these cells. Furthermore, blockage of CMA leads to hyperphosphorylation and destabilization of the MRN (Mre11–Rad50–Nbs1) complex, which participates in early steps of particular DNA repair pathways. We propose that CMA contributes to maintain genome stability by assuring nuclear proteostasis. Chaperone-mediated autophagy (CMA) helps maintain protein quality during cellular stress. Here the authors show that CMA is also activated in response to DNA damage and regulates degradation of the cell cycle regulator Chk1—the first nuclear protein shown to be a substrate of CMA.

Lipid droplets (LDs), initially considered “inert” lipid deposits, have gained during the last decade the classification of cytosolic organelles due to their defined composition and the multiplicity of specific cellular functions in which they are involved. The classification of LD as organelles brings along the need for their regulated turnover and recent findings support the direct contribution of autophagy to this turnover through a process now described as lipophagy. This paper focuses on the characteristics of this new type of selective autophagy and the cellular consequences of the mobilization of intracellular lipids through this process. Lipophagy impacts the cellular energetic balance directly, through lipid breakdown and, indirectly, by regulating food intake. Defective lipophagy has been already linked to important metabolic disorders such as fatty liver, obesity and atherosclerosis, and the age-dependent decrease in autophagy could underline the basis for the metabolic syndrome of aging.

The activation of mostly quiescent haematopoietic stem cells (HSCs) is a prerequisite for life-long production of blood cells 1 . This process requires major molecular adaptations to allow HSCs to meet the regulatory and metabolic requirements for cell division 2 – 4 . The mechanisms that govern cellular reprograming upon stem-cell activation, and the subsequent return of stem cells to quiescence, have not been fully characterized. Here we show that chaperone-mediated autophagy (CMA) 5 , a selective form of lysosomal protein degradation, is involved in sustaining HSC function in adult mice. CMA is required for protein quality control in stem cells and for the upregulation of fatty acid metabolism upon HSC activation. We find that CMA activity in HSCs decreases with age and show that genetic or pharmacological activation of CMA can restore the functionality of old mouse and human HSCs. Together, our findings provide mechanistic insights into a role for CMA in sustaining quality control, appropriate energetics and overall long-term HSC function. Our work suggests that CMA may be a promising therapeutic target for enhancing HSC function in conditions such as ageing or stem-cell transplantation. Haematopoietic stem cells show progressive functional decline with age that can be reversed by stimulation of chaperone-mediated autophagy in old mice and aged humans.