*3.1.1. Glucose supply*

With the complete interruption of or decrease in blood flow, the extracellular concentration of glucose drops very quickly. First, the cell optimizes the uptake of glucose from the inter‐ stitial space by improving glucose transmembrane transport by increasing the sarcoplasmic expression of the high-affinity glucose transporters GLUT-1 and GLUT-4. [6]-[8] This protec‐ tive mechanism temporarily compensates for the decrease in extracellular glucose concen‐ tration. Next, the cell uses its intracellular glucose stores of glycogen. [9] The decrease in intracellular ATP and glucose-6-phosphate, the rising lactate/pyruvate ratio and the increase in intracellular AMP and the inorganic phosphate concentration activate a phosphorylase kinase, which catalyses the conversion of glycogene phosphorylase b to its active form, gly‐ cogene phosphorylase a. This cascade reaction leads to an intense and rapid consumption of glycogen. [10]-[14]

### *3.1.2. Glycolysis pathways*

The inhibition of oxidative phosphorylation caused by lack of oxygen does not allow the pyruvate produced by glycolysis to be degraded. Under aerobic conditions, pyruvate is transported into the mitochondria and feeds into the Krebs cycle, which provides the nicoti‐ namide adenine dinucleotide (NADH, H+ ) and flavine adenine dinucleotide (FADH2) cofac‐ tors for oxidative phosphorylation, significantly increasing the yield of glycolysis.

Ischemia modulates the activity of the following two key enzymes of anaerobic glycolysis: phosphofructo-1-kinase (PF1K) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH).

Following the onset of ischemia, or during moderate ischemia, the activation of glycogenol‐ ysis accelerates glycolysis.[15]-[17] The decrease in both intracellular ATP and creatine phos‐ phate, along with increases in the intracellular concentrations of AMP, inorganic phosphate and fructose-1,6-bisphosphate, intensify the activity of PF1K and GAPDH. [17]-[20]

During prolonged or sustained ischemia, the low intracellular glucose concentration, the disappearance of glycogen and severe intracellular acidosis eventually inhibit PF1K. Fur‐ thermore, high concentrations of lactate and protons in ischemic tissues also inhibit GAPDH. [21],[22]

Moreover, the lactate/pyruvate ratio, intracellular acidosis and the absence of regenerated essential cofactors, such as NADH,H+ , affect the catalytic activity of the other enzymes in‐ volved in the initial step of glycolysis and prevent the optimal performance of anaerobic glycolysis. [23]

dehydrogenase and 3-hydroxyacyl-CoA dehydrogenase, which are key beta-oxidation enzymes.[4],[25] The cytosolic concentrations of fatty acids, acyl-CoA and acylcarnitine rise gradually. [26]-[28] The accumulation of these amphiphilic compounds in ischemic tissues has major functional implications. They dissolve readily in cell membranes and affect the functional properties of membrane proteins. Decreased activity of Na+/K+-ATPase and the sarcoplasmic and endoplasmic reticulum Ca2+-ATPase pumps, as well as the activation of ATP-dependent potassium channels, reduces the inwardly rectifying potassium current and prolongs the opening of Na+ channels, delaying their inactivation.[29]-[31] The accumulation of amphiphilic compounds produces a time-

Figure 2. This figure shows schematically oxidative metabolism, ATP production and the consequences of oxygen deprivation. GLUT-1 and GLUT-4: glucose transporters; GP: Glycogene phosphorylase; HK: Hexokinase; PF1K: Phosphofructo-1-kinase; GADPH: glyceraldehyde-3 phosphate dehydrogenase; NADH, H+: nicotinamide adenine dinucleotide; FADH2: flavine adenin dinucleotide; P: phosphate;AMP, adenosine monophosphate; adenosine diphosphate;ADP: adenosine diphosphate ATP: adenosine triphosphate; CO2 : carbon dioxide; O2 Oxygen; - :

H+

Hypoxia -

H+ H+

CO2

NADH+H+

NADH+H+

FADH2

Acetyl-Co A

*Krebs cycle* 

*-oxydation*

Fatty Acid

Fatty Acid

ATP

CO2 CO2

*in out* 7

Impact of Ischemia on Cellular Metabolism http://dx.doi.org/10.5772/54509

Pyruvate

H+


Glycogen

Fasting Hypoxia +

H+

H+

GLUT-1 GLUT-4 Glucose

Glucose

Fructose-6-P

Fructose-1-6-P

1,3-diphosphoglycerate

GADPH

PF1K

Pyruvate

Glucose-6-P -

HK

GP

Glucose

H+ H+

H+

H+

ADP Pi

ADP Pi

ATP H+

ATP H<sup>+</sup>

H+

H+

H<sup>+</sup> H<sup>+</sup>

2e-

H+ H+

H+

H+

H+ H+ H+

**Figure 2.** This figure shows schematically oxidative metabolism, ATP production and the consequences of oxygen deprivation. GLUT-1 and GLUT-4: glucose transporters; GP: Glycogene phosphorylase; HK: Hexokinase; PF1K: Phospho‐ fructo-1-kinase; GADPH: glyceraldehyde-3-phosphate dehydrogenase; NADH, H+: nicotinamide adenine dinucleotide; FADH2: flavine adenin dinucleotide; P: phosphate;AMP, adenosine monophosphate; adenosine diphosphate;ADP: ad‐ enosine diphosphate ATP: adenosine triphosphate; CO2 : carbon dioxide; O2 Oxygen; - : inhibition; + activation; H+:

H+

*Electron transport chain and creation of H+ gradient* 

<sup>H</sup><sup>+</sup> <sup>H</sup><sup>+</sup>

H+

dependent reversible reduction in gap-junction conductance. [31]

*Sarcoplasmic membrane* 

Interstitium

inhibition; + activation; H+: proton; e-

 *Inner membrane Intermembrane space Outer membrane* 

*mitochondrion* 

: electron.

proton; e-

*metabolism* 

: electron.

**3.3. Metabolite detoxification pathways** 

ATP

ATP

Hypoxia, AMP, ADP Insulin

> - Lactate, NADPH2 NADPH+H+

ATP, citrate, free fatty acid

+

pH -

Hypoxia

Lactate

+

#### **3.2. Lipid metabolism (Figure 2)**

The importance of oxygen in functional oxidative phosphorylation leads to a significant reduction in ATP production from the beta-oxidation of fatty acids that is proportional to the degree of ischemia. In mild to moderate ischemia, the rate of fatty acid oxidation decreases but still fuels oxidative phosphorylation. [4],[24] In more severe ischemia, the lack of the cofactors NADH,H+ and FAD+ , which are normally regenerated through oxi‐ dative phosphorylation, completely inhibits acyl-CoenzymeA (acyl-CoA) dehydrogenase and 3-hydroxyacyl-CoA dehydrogenase, which are key beta-oxidation enzymes.[4],[25] The cytosolic concentrations of fatty acids, acyl-CoA and acylcarnitine rise gradually. [26]-[28] The accumulation of these amphiphilic compounds in ischemic tissues has ma‐ jor functional implications. They dissolve readily in cell membranes and affect the func‐ tional properties of membrane proteins. Decreased activity of Na+ /K+ -ATPase and the sarcoplasmic and endoplasmic reticulum Ca2+-ATPase pumps, as well as the activation of ATP-dependent potassium channels, reduces the inwardly rectifying potassium current and prolongs the opening of Na+ channels, delaying their inactivation.[29]-[31] The accu‐ mulation of amphiphilic compounds produces a time-dependent reversible reduction in gap-junction conductance. [31]

#### **3.3. Metabolite detoxification pathways**

Reducing the intracellular concentration of ATP inhibits the hexose phosphate cycle. This metabolic pathway regenerates glutathione, ascorbic acid and tocopherol, which are involved in the detoxification of metabolites from the cytosol and the sarcoplasmic membrane.
