Glucose induces autophagy under starvation conditions by a p38 MAPK-dependent pathway.
2013
Autophagy is a natural process of ‘self-eating’ that occurs within cells and can be either pro-survival or can cause cell death. As a pro-survival mechanism, autophagy obtains energy by recycling cellular components such as macromolecules or organelles. In response to nutrient deprivation, e.g. depletion of amino acids or serum, autophagy is induced and most of these signals converge on the kinase mTOR (mammalian target of rapamycin). It is commonly accepted that glucose inhibits autophagy, since its deprivation from cells cultured in full medium induces autophagy by a mechanism involving AMPK (AMP-activated protein kinase), mTOR and Ulk1. However, we show in the present study that under starvation conditions addition of glucose produces the opposite effect. Specifically, the results of the present study demonstrate that the presence of glucose induces an increase in the levels of LC3 (microtubule-associated protein 1 light chain)-II, in the number and volume density of autophagic vacuoles and in protein degradation by autophagy. Addition of glucose also increases intracellular ATP, which is in turn necessary for the induction of autophagy because the glycolysis inhibitor oxamate inhibits it, and there is also a good correlation between LC3-II and ATP levels. Moreover, we also show that, surprisingly, the induction of autophagy by glucose is independent of AMPK and mTOR and mainly relies on p38 MAPK (mitogen-activated protein kinase).
Abbreviations: ACC, acetyl-CoA carboxylase; ATF-2, activating transcription factor-2; ATG/Atg, autophagy-related gene; AMPK, AMP-activated protein kinase; CREB, cAMP-response-element-binding protein; DAPI, 4′,6-diamidino-2-phenylindole; DMEM, Dulbecco's modified Eagle's medium; 4E-BP1, eukaryotic initiation factor 4E-binding protein 1; ECACC, European Collection of Animal Cell Cultures; ERK1/2, extracellular-signal-regulated kinase 1/2; FBS, fetal bovine serum; HEK, human embryonic kidney; KH, Krebs–Henseleit; LC3, microtubule-associated protein 1 light chain; MAPK, mitogen-activated protein kinase; MEF, mouse embryonic fibroblast; MEM, minimum essential medium; MK, MAPK-activated protein kinase; MKK, MAPK kinase; mTOR, mammalian target of rapamycin; P-, phosphorylated-; p38IP, p38-interacting protein; PI3K, phosphoinositide 3-kinase; p70S6K, p70 S6 kinase; RNAi, RNA interference; siRNA, small interfering RNA
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