Autophagy in toxicology: self-consumption in times of stress and plenty

Abstract

Autophagy is a critical cellular process orchestrating the lysosomal degradation of cellular components in order to maintain cellular homeostasis and respond to cellular stress. A growing research effort over the last decade has proven autophagy to be essential for constitutive protein and organelle turnover, for embryonic/neonatal survival and for cell survival during conditions of environmental stress. Emphasizing its biological importance, dysfunctional autophagy contributes to a diverse set of human diseases. Cellular stress induced by xenobiotic exposure typifies environmental stress, and can result in the induction of autophagy as a cytoprotective mechanism. An increasing number of xenobiotics are notable for their ability to modulate the induction or the rate of autophagy. The role of autophagy in normal cellular homeostasis, the intricate relationship between cellular stress and the induction of autophagy, and the identification of specific xenobiotics capable of modulating autophagy, point to the importance of the autophagic process in toxicology. This review will summarize the importance of autophagy and its role in cellular response to stress, including examples in which consideration of autophagy has contributed to a more complete understanding of toxicant-perturbed systems.

Figure 1

Primary autophagic pathways in mammalian cells. Macroautophagy involves the sequestration of cytoplasmic components by the generation of a denovo double membrane structure (phagophore) from within the cell to form an autophagosome. The newly formed autophagosome then fuses with a lysosome, forming an autolysosome, where lysosomal hydrolases degrade the cellular components. Microautophagy mediates the sequestration of cellular cargo, proteins and organelles through the invagination of the lysosomal membrane. Once cellular components are localized in the lysosome, lysosomal hydrolases degrade the components. Chaperone Mediated Autophagy (CMA) involves the specific targeting and shuttling of individual proteins to the lysosome for degradation. Internalization of substrate proteins into the lysosome is mediated through coordinated interaction of chaperone proteins and the lysosomal receptor Lamp2a on the membrane of the lysosome.