Lysosomal positioning coordinates cellular nutrient responses

Abstract

Mammalian target of rapamycin (mTOR) signalling and macroautophagy (henceforth autophagy) regulate numerous pathological and physiological processes including cellular responses to altered nutrient levels. However, the mechanisms regulating mTOR and autophagy remain incompletely understood. Lysosomes are dynamic intracellular organelles 1, 2 intimately involved both in the activation of mTOR complex 1 (mTORC1) signalling and in degrading autophagic substrates 3-8. Here we report that lysosomal positioning coordinates anabolic and catabolic responses to changes in nutrient availability by orchestrating early plasma membrane signalling events, mTORC1 signalling and autophagy. Activation of mTORC1 by nutrients correlates with its presence on peripheral lysosomes that are physically close to the upstream signalling modules, while starvation causes perinuclear clustering of lysosomes, driven by changes in intracellular pH (pHi). Lysosomal positioning regulates mTORC1 signalling, which, in turn, influences autophagosome formation. Lysosome positioning also influences autophagosome-lysosome fusion rates, and thus controls autophagic flux by acting both at the initiation and termination stages of the process. Our findings provide a fundamental physiological role for the dynamic state of lysosomal positioning in cells as a coordinator of mTORC1 signalling with autophagic flux.

Defective recruitment of motor proteins to autophagic compartments contributes to autophagic failure in aging

“…As previously described (Korolchuk et al., 2011), we found that upon removal of serum, the fraction of AVs in the perinuclear region increased about twofold in the fibroblasts from young mice. However, this juxtanuclear relocalization was severely blunted in old mice fibroblasts(Figure 2a,b).…”

“…In agreement with our steady‐state observations, movement of autophagic vesicles toward the cellular periphery was significantly greater in primary fibroblasts from old mice than from young mice (Figure 3h). Serum removal did not significantly change the overall motility of APG in young cells (Figure 3i,j) but, as previously described (Korolchuk et al., 2011), it switched their microtubule directionality toward the perinuclear area (Figure 3k). Removal of serum in fibroblasts from old animals resulted in a significant increase in APG motility (Figure 3i,j) and partially reverted the directionality of these vesicles (Figure 3k).…”

“…In recent years, an mTORC1‐dependent mechanism has been proposed to modulate the lysosomal positioning during nutritional stress (Korolchuk et al., 2011) but the molecular mechanisms underlying the redistribution of lysosomal compartment remain unknown. Our study suggests that lysosomal association of KIFC3 plays a major role in the retrograde movement of lysosomes and that reduced recruitment of this motor with age contributes, at least partially, to lower autophagy.…”

Spatio‐Temporal Parameters of Endosomal Signaling in Cancer: Implications for New Treatment Options

“…Important for the spatial regulation of endosomal signaling, we are addressing in this review, is a finding described a few years ago that lysosomal positioning regulates the protein kinase complex mTORC1 activity [Korolchuk et al, 2011]. It was shown in this study that lysosomes move more closely to the plasma membrane in response to nutrient availability, whereas starvation causes perinuclear clustering of the organelles facilitating autophagy.…”

The autophagy conundrum in cancer: influence of tumorigenic metabolic reprogramming

“…Finally, the presence of amino acids allows the activation of mTOR by Rheb, in part through the Rag GTPase-mediated translocation of mTOR to the lysosomal surface (Sancak et al, 2010). Amino-acid starvation, which inhibits mTOR, also facilitates autophagosome-lysosome fusion through lysosome clustering (Korolchuk et al, 2011).…”