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BioMed Research International
Volume 2013 (2013), Article ID 942431, 9 pages
http://dx.doi.org/10.1155/2013/942431
Research Article

Depletion of Luminal Pyridine Nucleotides in the Endoplasmic Reticulum Activates Autophagy with the Involvement of mTOR Pathway

Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, Tűzoltó utca 37-47, Budapest 1094, Hungary

Received 6 July 2013; Revised 3 October 2013; Accepted 7 October 2013

Academic Editor: Cristina Angeloni

Copyright © 2013 Orsolya Kapuy and Gábor Bánhegyi. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

It has been recently shown that redox imbalance of luminal pyridine nucleotides in the endoplasmic reticulum (ER) together with oxidative stress results in the activation of autophagy. In the present study we demonstrated that decrease of luminal NADPH/NADP+ ratio alone by metyrapone was sufficient to promote the mechanism of “self-eating” detected by the activation of LC3. Depletion of luminal NADPH had also significant effect on the key proteins of mTOR pathway, which got inactivated by dephosphorylation. These findings were also confirmed by silencing the proteins (glucose-6-phosphate transporter and hexose-6-phosphate dehydrogenase) responsible for NADPH generation in the ER lumen. However, silencing the key components and addition of metyrapone had different effects on downstream substrates 4EBP1 and p70S6K of mTOR. The applied treatments did not compromise the viability of the cells. Our data suggest that ER stress caused by luminal NADPH depletion activates a pro-survival autophagic mechanism firmly coupled to the activation of mTOR pathway.