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protein misfolding, which is a potent trigger of both processes. However,
cross talk between the UPR and master metabolic regulators has received
little attention until recently. AMPK has been shown to require the endori-
bonuclease activity of IRE1 for nitric oxide-induced signaling ( Meares
et al., 2011 ). Moreover, stimulation of the IRE1 endoribonuclease activity
with the flavonoid quercetin also engages IRE1-dependent AMPK activa-
tion. This signaling pathway is important for maintaining cellular metabo-
lism because it regulates the activity of critical proteins, such as acetyl-CoA
carboxylase, PGC-1α and mTORC1. This cooperative effect is of particular
interest in tissues with high metabolic activity, such as the heart. The AMPK
activators AICAR or metformin relieve hypoxia/reoxygenation injury, a
process known to trigger apoptosis in cardiomyocytes, by generating ER
stress ( Yeh et al., 2010 ). This response is achieved by the concomitant
decrease in proapoptotic branches of the UPR (CHOP and caspase-12)
while retaining an adaptive increase in BiP/GRP78 protein levels. Taken
together, this evidence suggests that AMPK signaling may cooperate with,
or even be part of the adaptive steps of UPR, by diminishing death-induc-
ing irreparable damage. However, many details of this complex cross talk
process still need to be unraveled.
When ER stress is induced by increased protein load, instead of
decreased nutrients, the role of mTOR has been shown to be important.
Such is the case for plasma cells, which secrete large amounts of immuno-
globulins when they are stimulated with LPS. These cells, upon induction
of ER stress, attenuate the mTOR pathway, leading to reduced protein
synthesis. This reduction is important for cellular adaptation as B cells with
elevated mTOR activity are prone to undergo apoptosis upon LPS stimu-
lation ( Goldfinger et al., 2011 ). A second example that shows the prepon-
derance of mTOR during ER stress has been established in a rat model
of minimal-change disease, which is characterized by podocyte ER stress-
dependent proteinuria. In this model, mTORC1 activation was shown to
precede UPR, leading to a decrease in the ATP/ADP ratio and activation
of AMPK, presumably due to an increase in energy-consuming processes,
such as cell growth and proliferation. Pretreatment with the mTORC1
inhibitor, everolimus, prevented the reduction in ATP levels, AMPK acti-
vation and UPR, thus inhibiting proteinuria ( Ito et al., 2011 ). Studies in
tumor cells have shown that constitutive activation of mTOR induces ER
stress, which is part of a negative feedback loop emerging from growth
factor receptors upstream of mTOR ( Ozcan et al., 2008 ). On the other
hand, during ER stress, mTORC1 triggers apoptosis by suppressing Akt
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