**2. Adenosine triphosphate depletion**

Eukaryotic cells contain mitochondria, organelles whose main function is to produce adeno‐ sine triphosphate (ATP). ATP is an essential energy substrate, as its hydrolysis provides en‐ ergy for many metabolic and biochemical reactions involved in development, adaptation and cell survival. ATP production in an aerobic cell is particularly effective when the degra‐ dation of key nutrients such as glucose and fatty acids is coupled to a supramolecular com‐ plex located in the inner membrane of mitochondria to drive oxidative phosphorylation. Oxidative phosphorylation is mediated by an electron transport chain that consists of four protein complexes and establishes a transmembrane electrochemical gradient by supporting the accumulation of protons in the intermembrane space of the mitochondria. This gradient is used as an energy source by ATP synthase during the synthesis of an ATP molecule from a molecule of adenosine diphosphate (ADP) and an inorganic phosphate (Figure 1). Without oxygen, oxidative phosphorylation stops: the proton gradient between the intermembrane space and the inner mitochondria is abolished, and ATP synthesis is interrupted. The ensu‐ ing rapid fall in intracellular ATP induces a cascade of events leading to reversible cell dam‐ age. However, over time, the damage increases and gradually becomes irreversible, which may lead to cell death and destruction of the parenchymal tissue.

**3.1. Glucose metabolism**

*3.1.1. Glucose supply*

glycogen. [10]-[14]

GAPDH. [21],[22]

*3.1.2. Glycolysis pathways*

namide adenine dinucleotide (NADH, H+

During ischemia, the cell will change not only its glucose supply routes but also its glycoly‐ sis pathways and transition from aerobic glycolysis to anaerobic glycolysis. When this hap‐ pens, the available cytosolic glucose is metabolized by anaerobic glycolysis and becomes the main source of ATP. The efficiency of this process is much lower than that of aerobic glycol‐ ysis coupled to oxidative phosphorylation; the anaerobic degradation of one molecule of glucose produces 2 ATP molecules compared to the 36 ATP molecules that are produced un‐ der aerobic conditions. Consumption quickly exceeds production, and the intracellular con‐ centration of ATP decreases. For example, in the heart, the degree of glycolysis inhibition is

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

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‐

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

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

tors for oxidative phosphorylation, significantly increasing the yield of glycolysis.

and fructose-1,6-bisphosphate, intensify the activity of PF1K and GAPDH. [17]-[20]

) and flavine adenine dinucleotide (FADH2) cofac‐

Impact of Ischemia on Cellular Metabolism http://dx.doi.org/10.5772/54509 5

directly proportional to the severity of coronary flow restriction.[3]-[5]

**Figure 1.** Hydrolysis of Adenosine-triphosphate provides energy (30.5 kJ per mole) for biochemical reactions

When devoid of ATP, the cell derives its energy from the pyrophosphate bonds of ADP as they are degraded to adenosine monophosphate (AMP) and then to adenosine. Adenosine diffuses freely out of the cell, dramatically reducing the intracellular pool of adenine nucleo‐ tides, the precursors for ATP.
