Abstract
Energy sensing is indispensable to balance anabolic and catabolic processes for the maintenance of cell viability. Pancreatic β cells are especially relevant because of their involvement in the coordination of insulin secretion when glucose concentration arises in the local milieu. In this work, we uncover the increased susceptibility of pancreatic β cells to cell death in response to different energy stressors. Upon glucose decline, from 25 to 5 mM, caused by stimulation with either 2-deoxyglucose or metformin, only pancreatic β cells showed an increase in cell death. Very interestingly, when we transfected either mouse insulinoma cell or human embryo kidney cells with a phospho-mutant form of B cell lymphoma 2 associated agonist of cell death at serine 155 (BAD S155D), an increase in the pro-survival factor B cell lymphoma 2 was detected in pancreatic β cells and not in human embryonic kidney cells in the presence of the energetic stressors. This data suggests that the protective capacity of this mutant form is only present in cells that present glucokinase. In contrast, upon hyperactivation of mechanistic target of rapamycin complex 1 signaling by knocking-down tuberous sclerosis complex protein, we observed increased susceptibility to cell death in response to energy stress in both pancreatic and non-pancreatic β cells. Therefore, mechanistic target of rapamycin complex 1 signaling presents a dual effect on cell viability. On the one hand, a chronic inhibition of mechanistic target of rapamycin complex 1 activity in response to the energy status is deleterious for pancreatic β cells, being attenuated by the overexpression of B cell lymphoma 2 associated agonist of cell death S155D. On the other hand, mechanistic target of rapamycin complex 1 hyperactivity provokes a susceptibility to energetic stress-induced cell death. Taken together, these results may open potential implications for the use of glucokinase activators or mechanistic target of rapamycin complex 1 modulators for the maintenance of pancreatic β cells for longer periods of time avoiding its loss in different pathologies such as type 2 diabetes mellitus.
Highlights
The mechanistic target of rapamycin (MTOR) is a serine–threonine protein kinase that belongs to the PI3Krelated kinase family[1]
In fibroblasts, the inhibition of MTORC1 is defined by its catalytic subunit (mTOR) complex 1 (MTORC1) activity occurred at a glucose concentration below 5 mM, AMPK activation was very efficient in all the conditions of glucose concentration (Fig. 1a)
In response to 2DG, only MIN6 cells were capable to down-regulate MTORC1 signaling with a concomitant increase in AMPK signaling (Fig. 2a)
Summary
The mechanistic target of rapamycin (MTOR) is a serine–threonine protein kinase that belongs to the PI3Krelated kinase family[1]. It regulates eukaryotic cell growth and metabolism in response to stimuli, including nutrients and growth factors comprising the catalytic subunit. TSC2 presents a GTPase activating protein (GAP) domain, which enables RHEB to inhibit MTORC1 and it is recruited to the surface of the lysosome in response to multiple stress signals: low energy, hypoxia, amino-acid starvation, hyperosmotic stress, and others[5,6,7]. Glucokinase (GK) is a glycolytic enzyme present in β cells and hepatocytes, associated to the BCL-2 family proapoptotic protein BAD at the mitochondrial membrane[8,9]. When BAD protein is phosphorylated on Ser 155, GK is capable of stimulating β cells to secrete insulin and improve their function and survival[10]
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