Mol Cell. 2026 Jan 28. pii: S1097-2765(26)00031-6. [Epub ahead of print]
Lysosomes are hubs that couple macromolecular breakdown to cell-wide signaling by sensing metabolic, damage-associated, and environmental cues. Nutrients liberated in the lysosomal lumen as end-products of macromolecular degradation, including amino acids, lipids, and iron, are exported by dedicated transporters for utilization in the cytoplasm. Nutrient transport across the lysosomal membrane is coupled to its sensing by specialized signaling complexes on the cytoplasmic face, which, in response, mediate communication with other organelles and control cell-wide programs for growth, catabolism, and stress response. Lysosomes acquire specialized sensing-signaling features in immune cells, where they shape antigen processing, innate immune signaling, and inflammatory cell death, and in neurons, where they act as sentinels of proteostatic and mitochondrial stress, supporting local translation, organelle quality control, and neuroimmune crosstalk. We highlight recently identified pathways and players that position lysosomes as integrators of nutrient status and organelle health to drive tissue-specific physiology.
Keywords: amyloid; autophagy; inflammation; lysosome; mTORC1; metabolites; neurodegeneration; organelle contacts; signaling