Lysosomes: Signaling Hubs for Metabolic Sensing and Longevity.

Lysosomes are sites of active metabolism in a cell. They contain various hydrolases that degrade extracellular and intracellular materials during endocytosis and autophagy, respectively. In addition to their long-recognized roles in degradation and recycling, emerging studies have revealed that lysosomes are organizing centers for signal transduction. Lysosome-derived signaling plays crucial roles in regulating nutrient sensing, metabolic adaptation, organelle crosstalk, and aging. In particular, how the degradative role of the lysosome cooperates with its signaling functions to actively modulate lifespan is beginning to be unraveled. This review describes recent advances in the role of the lysosome as a 'signaling hub' that uses three different lysosome-derived signaling pathways to integrate metabolic inputs, organelle interactions, and the control of longevity. The lysosome serves as a signaling center to integrate extracellular and intracellular inputs, and accordingly regulates cellular homeostasis and organism fitness. mTORC1 at the lysosomal surface responds to amino acid and cholesterol signals from the lysosomal lumen, and coordinates downstream pathways involved in aging control. AMPK is recruited to the lysosomal surface for activation in response to glycolytic signals, and promotes longevity via specific downstream effectors. Specific lipid messengers and chaperones mediate lysosome-to-nucleus retrograde signaling communication to improve interorganelle crosstalk, redox homeostasis, and longevity. [ABSTRACT FROM AUTHOR]