Possible Involvement of the Nutrient and Energy Sensors mTORC1 and AMPK in Cell Fate Diversification in a Non-Metazoan Organism

Abstract

mTORC1 and AMPK are mutually antagonistic sensors of nutrient and energy status that have been implicated in many human diseases including cancer, Alzheimer’s disease, obesity and type 2 diabetes. Starved cells of the social amoeba Dictyostelium discoideum aggregate and eventually form fruiting bodies consisting of stalk cells and spores. We focus on how this bifurcation of cell fate is achieved. During growth mTORC1 is highly active and AMPK relatively inactive. Upon starvation, AMPK is activated and mTORC1 inhibited; cell division is arrested and autophagy induced. After aggregation, a minority of the cells (prestalk cells) continue to express much the same set of developmental genes as during aggregation, but the majority (prespore cells) switch to the prespore program. We describe evidence suggesting that overexpressing AMPK increases the proportion of prestalk cells, as does inhibiting mTORC1. Furthermore, stimulating the acidification of intracellular acidic compartments likewise increases the proportion of prestalk cells, while inhibiting acidification favors the spore pathway. We conclude that the choice between the prestalk and the prespore pathways of cell differentiation may depend on the relative strength of the activities of AMPK and mTORC1, and that these may be controlled by the acidity of intracellular acidic compartments/lysosomes (pHv), cells with low pHv compartments having high AMPK activity/low mTORC1 activity, and those with high pHv compartments having high mTORC1/low AMPK activity. Increased insight into the regulation and downstream consequences of this switch should increase our understanding of its potential role in human diseases, and indicate possible therapeutic interventions.

Polycystin-2 Mediated Calcium Signalling in the Dictyostelium Model for Autosomal Dominant Polycystic Kidney Disease

“…PC2 activity is also essential for inducing autophagy under hyperosmotic stress in HeLa and HCT116 cells via the mTOR pathway [80]. These parallels with our findings confirm that Dictyostelium is an ideal model for studying autophagy and autophagic cell death [82,83], and given the extensive knowledge available AMPK and DdTOR signalling in Dictyostelium [38,[84][85][86][87], this model system offers invaluable opportunities to investigate Polycystin-2-regulated autophagy and the underlying signalling pathways.…”

The Anti-Obesity and Anti-Steatotic Effects of Chrysin in a Rat Model of Obesity Mediated through Modulating the Hepatic AMPK/mTOR/lipogenesis Pathways

“…The expression of AMPK and its upstream activating kinase (LKB1) was significantly suppressed, as well as p-AMPK and LKB1 protein levels in the liver, while the mTOR expression was markedly enhanced. AMPK and mTOR are mutually antagonistic nutrient sensors that have been associated with several metabolic diseases, such as NAFLD [ 33 ]. The phosphorylation of Tuberous sclerosis 2 (TSC2) and Raptor are both required for AMPK-mediated inhibition of mTORC1 [ 34 ].…”

Sequential events during the quiescence to proliferation transition establish patterns of follicle cell differentiation in the Drosophila ovary

“…Unambiguously positive effects of repeated Q→P transitions via caloric or nutrient restriction have been demonstrated for multiple stem cell populations ( Mana et al, 2017 ). However, concern has been raised regarding impact on differentiated cells, particularly in the context of tumorigenesis and cancer progression ( Clifton et al, 2021 ; Gross and Pears, 2021 ; Nowak et al, 2013 ; Wood et al, 2020 ). The fly germarium provides a new model for investigation of the effects of nutrient restriction cycles on both epithelial stem cells and their progeny, providing opportunities to delineate mechanisms that govern plasticity and differentiation status with broad implications.…”