Inhibition of chaperone-mediated autophagy and LAMP-2A localization by dietary lipids
A recent collaboration between the Albert Einstein College of Medicine, Columbia University, and National University of Singapore has recently published an interesting paper which explores the relationship between increases of dietary lipid intake and potential decreases to an important mechanism of organismal cell death which has been previously associated with disorders such as Parkinson’s disease and a number of tauopathies. Through this study, the authors provide evidence that high levels of certain forms of fat in a person’s diet may play an important role in the regulation of chaperone-mediated autophagy, which constitutes an essential physiological process in the development and survival of most organisms.
In the majority of mammalian species, autophagy serves as an important modulator of the normal development and controlled death of tissues, through its roles in the recycling of intracellular components, dismantling of poorly functioning cells, and reallocation of important nutrients in the body. This process typically involves the activity of intracellular lysosomes, which are acidic organelles filled with hydrolase enzymes that catabolize the cellular components which they have engulfed. Most notably, this mechanism of controlled cell death has been previously investigated for its role in immune responses, the development of various carcinomas, as well as various forms of neurodegeneration. Regardless of the context, autophagic molecular cascades seem to be consistently activated following exposure to various cellular stressors, including nutrient starvation, hypoxia, or jeopardized DNA integrity. Though a gross oversimplification, this process may be thought of as a mechanism for “damage control” in most cells.
In the recent study, which was published in the March 20th edition of PNAS, the research team investigated a specific subtype of this form of cell death, known as chaperone-mediated autophagy (CMA). CMA is characterized by the specific recognition and degradation of intracellular proteins which contain a unique recognition domain. This domain is integral for the binding of these proteins to chaperone molecules which guide the proteins to the lysosomal machinery; once there, the proteins associate with another mediator known as lysosome-associated membrane protein type 2A (LAMP-2A), which passes the protein into the lysosome for degradation. In previous studies, it has been observed that the extent to which CMA occurs in cells can be modulated through alterations of not only the amount of LAMP-2A which is present, but the specific intracellular localization of LAMP-2A as well. As an organism ages, levels of LAMP-2A in the lysosomal membrane (and thus normal CMA levels) begin to slowly decrease in most tissues, and similar declines can also be observed throughout the development of numerous neurodegenerative disorders.
To determine whether changes to lipid intake could affect the process of CMA, the research team used a combination of cell culture and mouse models to demonstrate that “lipid challenges” could affect this relationship in normal cellular functioning. In the given context, the term “lipid challenges” simply referred to increases in dietary fats and cholesterols compared to normal intake. In the cell culture models, increased levels of oleate (a fatty acid component of olive oil) appeared to inhibit the observed patterns of basal CMA, potentially through disruption of the normal levels of cholesterol which exist in the lysosomal membrane. In the animal models, mice were each fed one of several diets which differed in their cholesterol and overall fat content; the results appeared to parallel those from the in vitro studies, indicating that a reduction in CMA was indeed occurring.
Ultimately, the authors of the study explain their findings by suggesting that increases in dietary lipid levels can greatly reduce the stability of the LAMP-2A protein in the lysosomal membrane. As this protein is necessary for the translocation of substrates into the lysosome, the reduction of CMA seems logical, and given that levels of both LAMP-2A and hsc70 (the heat shock chaperone which brings substrates to LAMP-2A) transcription did not change between treatment groups, this conclusion appears to be warranted. Additionally, it was observed that levels of LAMP-2A at the lysosomal membrane, changes to the composition of lysosomal lipid species, and overall levels of CMA were very similar between old mice and those which had been exposed to a diet high in lipid content. The authors suggest that this relationship may comprise a unique mechanism for modulation of cellular CMA responses which may be functionally lost as an organism ages normally.
Since a general decrease in CMA has been observed in a number of different human disease states, including diabetes, Parkinson’s disease and numerous disorders where tangles of “tau protein” occur abnormally, an increased understanding of the molecular mechanisms which underlie the modulation of this process should be greatly beneficial. Theoretically, by incorporating information concerning dietary lipid intake with previously obtained data concerning the loss of CMA with age, therapeutic interventions which could help delay such disorders may not be that far off.
For more information, see the original research article