Blog
About

5
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: not found
      • Article: not found

      Restoration of chaperone-mediated autophagy in aging liver improves cellular maintenance and hepatic function

      ,

      Nature Medicine

      Springer Science and Business Media LLC

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          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. 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, 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.

          Related collections

          Most cited references 18

          • Record: found
          • Abstract: found
          • Article: not found

          Autophagy: in sickness and in health.

          The degradation of intracellular components in lysosomes (autophagy) has recaptured the attention of cell biologists in recent years. The main reason for this renewed interest is the dissection of the molecular machinery that participates in this process, because the identification of new intracellular elements involved in autophagy has provided new tools to trace, quantify and manipulate autophagy in a growing number of organisms. As a result, a better understanding of the physiological roles of autophagy, the consequences of its malfunctioning and its participation in different pathological processes has emerged. This article reviews our current knowledge of the role of autophagy in disease and the efforts to reconcile its proposed dual function as both a cell protector and a cell killer.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            A role for a 70-kilodalton heat shock protein in lysosomal degradation of intracellular proteins.

            A 73-kilodalton (kD) intracellular protein was found to bind to peptide regions that target intracellular proteins for lysosomal degradation in response to serum withdrawal. This protein cross-reacted with a monoclonal antibody raised to a member of the 70-kD heat shock protein (hsp70) family, and sequences of two internal peptides of the 73-kD protein confirm that it is a member of this family. In response to serum withdrawal, the intracellular concentration of the 73-kD protein increased severalfold. In the presence of adenosine 5'-triphosphate (ATP) and MgCl2, the 73-kD protein enhanced protein degradation in two different cell-free assays for lysosomal proteolysis.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Oxidative stress and autophagy.

              Organisms respond to oxidative injury by orchestrating a stress response to prevent further damage. An increase in the intracellular levels of antioxidant agents, and at the same time the removal of already damaged components, are both part of the oxidative stress response. Lysosomes have been classically considered one of the main targets of the reactive oxygen species. In fact, the destabilization of the lysosomal membrane during oxidizing conditions promotes the leakage of the enzymes contained in these organelles and contributes to cellular damage. However, recent evidence supports a protective role of the lysosomal system, which can eliminate altered intracellular components through autophagy, at least in the first stages of oxidative injury. Consequently, activation of the main intracellular proteolytic systems, the ubiquitin/proteasome, and also the lysosomal/autophagic system occurs during the oxidative stress response. The opposing roles for the lysosomal system under oxidizing conditions are discussed in this review.
                Bookmark

                Author and article information

                Journal
                Nature Medicine
                Nat Med
                Springer Science and Business Media LLC
                1078-8956
                1546-170X
                September 2008
                August 10 2008
                September 2008
                : 14
                : 9
                : 959-965
                Article
                10.1038/nm.1851
                2722716
                18690243
                © 2008

                http://www.springer.com/tdm

                Comments

                Comment on this article