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concentration, and glucose transporters (GLUT1 and GLUT4) levels and trans-
location; (3) conditions for signaling activation: any stress that interferes with
ATP synthesis and readily affects the AMP:ATP ratio, e.g., interruption of blood
supply (ischemia); (4) physiological response (changes in the fluxome): activation
of glycolysis that increases ATP availability (Marsin et al. 2000 ) [see also Chap. 11
in this topic, Chap. 10 in Cortassa et al. ( 2012 ) and Fig. 2.2 for further explanation].
2.2.2 ROS-Signaling Networks
Redox signaling can be exemplified by the regulation of protein activity and the
transduction of signals to downstream proteins through oxidative modification of
reactive cysteine (Cys) residues by ROS (Finkel 2000 ; Paulsen and Carroll 2010 ).
Cellular functions can be signaled by ROS in essentially two ways (Fig. 2.3 ):
(1) through direct oxidation of specific Cys or (2) indirectly through changes in
the activity of kinases or phosphatases that in turn modulate protein phosphoryla-
tion. The switch-like nature of the sulfenic acid (SOH) and disulfides that are
formed after the initial reaction of a Cys thiolate with H 2 O 2 and by reaction of
SOH with neighboring Cys or reduced glutathione (GSH), explains their potential
to function as reversible modifications that regulate protein function, analogous to
phosphorylation (Haddad 2004 ). For example, myofilament activation and contrac-
tile function may be altered during oxidative stress by direct oxidative
modifications of specific sites on contractile proteins or by ROS-induced changes
in the activity of kinases or phosphatases that regulate sarcomeric protein phos-
phorylation (Santos et al. 2011 ; Sumandea and Steinberg 2011 ).
Another relevant example is given by the tumor suppressor protein p53, a
transcriptional factor that in response to environmental challenge (e.g., hypoxia,
oxidative stress) can sense cellular redox status. When p53 is oxidized by ROS its
DNA binding capacity is decreased (Sun et al. 2003 ). Thus, under stressful
conditions, ROS from the metabolome oxidizes p53: the latter when oxidized
decreases its DNA binding capacity (Sun et al. 2003 ) thus inhibiting gene expres-
sion (genome) (Fig. 2.3 ). In turn, p53 can influence the metabolome through
decreasing F2,6BP and glucose transporter levels that affect the fluxome by
diminishing glycolysis and stimulating mitochondrial respiration (Fig. 2.2 ) (Lago
et al. 2011 ). p53 is also able to interact with the AMPK signaling network inducing
its activation after inhibition of the nutrient-sensitive kinase mTORC1: these effects
are followed by induction of autophagy (Fig. 2.2 ).
2.2.3 Sensing H 2 O 2 through Cysteine Oxidation
Cells can “sense” changes in redox balance through the specific reactions of H 2 O 2
(D'Autreaux and Toledano 2007 ; Paulsen and Carroll 2010 ; Pourova et al. 2010 ;
Schroder and Eaton 2009 ). In proteins, the thiol side chain of the amino acid Cys is
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