The mammalian target of rapamycin complex 1 (mTORC1) integrates mitogenic and stress signals to control growth and metabolism. Activation of mTORC1 by amino acids and growth factors involves recruitment of the complex to the lysosomal membrane and is further supported by lysosome distribution to the cell periphery. Here, we show that translocation of lysosomes toward the cell periphery brings mTORC1 into proximity with focal adhesions (FAs). We demonstrate that FAs constitute discrete plasma membrane hubs mediating growth factor signaling and amino acid input into the cell. FAs, as well as the translocation of lysosome-bound mTORC1 to their vicinity, contribute to both peripheral and intracellular mTORC1 activity. Conversely, lysosomal distribution to the cell periphery is dispensable for the activation of mTORC1 constitutively targeted to FAs. This study advances our understanding of spatial mTORC1 regulation by demonstrating that the localization of mTORC1 to FAs is both necessary and sufficient for its activation by growth-promoting stimuli.

BackgroundIn response to oncogenic stress, the tumour suppressor protein p53 can induce the elimination of cells through induction of cell death or senescence, helping to restrain malignant progression. Conversely, under nutrient stress, p53 can protect cells by supporting metabolic adaptation. Many cancers express mutant p53 proteins that have lost the cell-elimination properties of wild-type p53. However, a previous report showed that a tumour-derived mutant can retain the ability to support cells under glutamine starvation.ResultsWe show that a commonly occurring p53 mutant, R248W, retains wild-type ability to support survival under serine starvation. R248W, but not R175H, can engage p21 and MDM2, which both function to limit oxidative stress and facilitate the switch to de novo serine synthesis. In vivo, the growth of R248W-expressing tumours is resistant to dietary depletion of serine and glycine, correlating with an increased capacity to limit ROS compared to tumours expressing R175H. Human cancers expressing this p53 mutant show a worse outcome.ConclusionOur work shows that mutant p53s can selectively retain wild-type p53 functions that allow adaptation to serine starvation through the activation of antioxidant defence pathways. Tumours containing this p53 mutation are resistant to serine-limited conditions and less responsive to therapy.Electronic supplementary materialThe online version of this article (10.1186/s40170-018-0191-6) contains supplementary material, which is available to authorized users.

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Mitochondrial reactive oxygen species (mtROS) are cellular messengers essential for cellular homeostasis. In response to stress, reverse electron transport (RET) through respiratory complex I generates high levels of mtROS. Suppression of ROS production via RET (ROS-RET) reduces survival under stress, while activation of ROS-RET extends lifespan in basal conditions. Here, we demonstrate that ROS-RET signalling requires increased electron entry and uninterrupted electron flow through the electron transport chain (ETC). We find that in old fruit flies, ROS-RET is abolished when electron flux is decreased and that their mitochondria produce consistently high levels of mtROS. Finally, we demonstrate that in young flies, limiting electron exit, but not entry, from the ETC phenocopies mtROS generation observed in old individuals. Our results elucidate the mechanism by which ROS signalling is lost during ageing.