Systems Level Regulation of Cardiac Energy Fluxes Via Metabolic Cycles: Role of Creatine, Phosphotransfer Pathways, and AMPK Signaling - Systems Biology of Metabolic and Signaling Networks - page 262

AcCoA /CoA ratios inhibit PDH. Their inhibitory effect is realized through pyru-
vate dehydrogenase kinase (PDK) that phosphorylates and inhibits PDH (Randle
1998 ). Citrate that escapes oxidation in the Krebs cycle is transported to the cytosol
where it inhibits PFK and glycolysis (Hue and Taegtmeyer 2009 ; Taegtmeyer 2010 ;
Taegtmeyer et al. 2005 ).
Cell signaling via AMPK provides a parallel control of most of these processes,
including substrate uptake via fatty acid and glucose transporters and flux via
β

-FAO and glycolysis (see Sect. 5.5 ). Activation of AMPK during energy stress
situations stimulates all these activities.
Physiologically, the significance of the Randle cycle is to ensure the provision of
FAs to high-energy demanding organs such as muscle and liver. Also, glucose is
directed to organs such as brain, red blood cells, and other tissues dependent upon
glucose oxidation and possessing relatively small stores of glycogen.

11.3.2 Which Substrate Is Better: Reductionism Versus
Systems Biology

Living cells extract and transform energy from different sources distributing them
between organs, as a function of their energy needs and metabolic potential.
Unfortunately, there is not yet consensus on evaluating the amount of energy that
may be extracted from different carbon sources. A reason for this is differences
between reductionistic and systems biology type of approaches. The reductionist
explanation of the competitive use of different energy sources by distinct organs is
based on the oxygen needed to oxidize the different substrates and considerations of
coupling of oxidative phosphorylation. All electrons from NADH produced in
aerobic catabolism (i.e., from glycolysis and fatty acid oxidation) enter the respira-
tory chain via complex I, or electrons from FADH 2 formed in -FAO are carried via

electron transferring flavoprotein and complex III (Fig. 11.4 ), resulting in lower
ATP/O ratio. In this way, the yield of 38 ATP for 12 atoms of oxygen consumed
(P/O

β

3.16) for glucose (C 6 H 12 O 6 ) oxidation and the yield of 129 ATP for
46 atoms of oxygen consumed (P/O

¼

2.8) for palmitic acid (C 16 H 32 O 2 ) oxidation
are assumed to be sufficient to conclude that glucose is the preferential fuel for
living organisms. This conclusion is further corroborated by measurements of
oxygen consumption by direct calorimetry. When one liter of oxygen is used to
burn substrates, the amount of energy obtained is 5.19 kcal/LO 2 for glucose and
4.81 kcal/LO 2 for palmitic acid (Leverve et al. 2006 ). However, these calculations

¼

Fig. 11.4 (continued) would inhibit hexokinase (HK), and decrease glucose transport. G6P
glucose 6-phosphate, HK hexokinase, PFK phosphofructokinase, GLY glycogen, F1,6diP fruc-
tose-1,6-bisphosphate, GAPDH glyceraldehyde 3 phosphate dehydrogenase, 1,3DPG 1,3
diphosphoglycerate. AMPK signaling (orange) controls among others substrate uptake and flux
via glycolysis and fatty acid oxidation under conditions of starvation, hypoxia and other triggers of
energy stress. For details see text. Modified from (Saks et al. 2012 ) with permission