The tissue-specific autophagic response to nutrient deprivation

Abstract

AbstractMacroautophagy is a highly adaptable degradative system that is essential for life. Although studies have shown the importance of this pathway across all organ systems, we have little understanding of how discrete tissues might employ autophagy and how this changes during stress. Using an approach to identify quantitatively autophagic cargoes, we sought to identify how cells from the adult liver and brain rely on autophagy under basal conditions and during nutrient deprivation. We find that in addition to the turnover of cell type specific proteins, the different organs relied on autophagy differentially for the turnover of organelles such as mitochondria, peroxisomes and ER. Moreover, in response to nutrient deprivation, although both tissues showed increased cargo capture, cell type- and tissue-specific patterns emerged. Most notably in the brain, we found an increased representation of glial and endothelial cell cargoes, whereas neuronal cargoes were relatively unchanged. In liver, we unexpectedly found a decreased representation of mitochondrial proteins, which represented a shift moving away from the whole mitochondrion turnover to piecemeal. These results indicate how the physiologic context of the different cell types significantly influence autophagy-dependence, and begins to shed insight into how the term ‘autophagy dysfunction’ might be thought of when considering different disease states.