111757 and disrupting the interaction of Ulk1 with AMPK (Kim et al. 2011 ). SIRT1
deficiency results in elevated mTOR signaling, and the SIRT1 activator resvera-
trol reduces mTOR activity in a SIRT1-dependent manner. SIRT1 interacts with
TSC2, a component of the mTOR inhibitory complex upstream to mTORC1,
and regulates mTOR signaling in a TSC2-dependent manner (Ghosh et al. 2010 ).
Paradoxically, RAP extends life span and increases insulin sensitivity, but the
chronic administration of RAP causes glucose intolerance and insulin resistance.
This phenomenon is now deciphered by that RAP disrupts a second mTOR com-
plex, mTORC2, which is required for the insulin-mediated suppression of gluco-
neogenesis. Suppression of mTORC1 signaling is sufficient to extend life span
independently from glucose homeostasis, so the effects of RAP on glucose home-
ostasis and longevity can be uncoupled (Lamming et al. 2012 ).
ROS and RNS can regulate autophagy, but how they are engaged in autophagy
remains obscure. Sarkar et al. ( 2011 ) have revealed a surprising autophagy-modu-
lating pattern by ONOO−-mediated S-nitrosylation of target proteins in mamma-
lian cells. ONOO− inhibits the autophagic flux by S-nitrosylation of the cysteine
residue of JNK1 or IKKβ, which leads to the failure of JNK1/IKKβ phosphoryla-
tion, and thereby allows the decrease of JNK1 activity and the abrogation of Bcl-2
phosphorylation, or the activation of mTORC1 upon inactivation of IKKβ, AMPK,
and TSC2 (Zeng 2013 ). From this knowledge, an integrated autophagy-controlling
network comprising both mTORC1 and SIRT1 signaling pathways can be summa-
rized (Fig. 7.1).
Fig. 7.1 The mechanism underlying NO-repressed autophagy. NO inhibits JNK1 phosphoryla-
tion by S-nitrosylation. Decrease of phospho-Bcl-2 and increase of Bcl-2-Beclin1 interaction
disrupt Vps34-Beclin1 association. NO also inhibits IKKb phosphorylation by S-nitrosylation.
Decrease of phospho-AMPK and TSC2 activity alleviate the inhibitory effect of TSC1/2 on Rheb
(denoted by “×”), thereby allowing Rheb to activate mTORC1 for inhibition of autophagy. RAP
induces autophagy by inhibiting mTORC1, whereas resveratrol and CR induces autophagy by
activating SIRT1 or inactivating mTORC1. SIRT1 accelerates mitochondrial biogenesis by acti-
vating PGC-1α
7.1 Nitrosylation/Nitration in the Active Center of Proteins ...