Abstract
Except of the simplified view of lysosomes as the final compartments of degradation process, lysosomes are increasingly regarded as upstream organelles in the control of cell functions. Therefore, lysosome homeostasis should be tightly regulated to match the catabolic needs as well as to maintain lysosomal pathways. Here we use light-induced mitophagy substrates to disturb lysosome homeostatsis and reveal how lysosome biogenesis responses quantitatively to different levels of degradation stress. We observed that TFEB-mediated lysosomal genes activation is upregulated in dose-dependent manner upon variants mitophagy degradation stresses. This stress-response coordination is quantitatively modulated by mTOR inactivation. We further show that mitophagy-dependent mTOR inactivation is mediated by spatially recruiting mTOR activity regulators, DEPDC5 and FLCN, on autolysosome, a hybrid organelle of autophagosome and lysosome. Also, blocking autophagosome-lysosome fusion, by knocking down STX17, makes TFEB activation response decoupling from stress. These results suggest lysosome and autolysosome are functionally different in respect of mTOR activity and TFEB activation. Through fusing with autophagosomes, lysosomes sense degradation stress and decode into fine-tuning TFEB activation in the maintenance of self-regulated homeostasis.