**4. Intracellular acidosis**

Intracellular acidosis is a cardinal feature of cellular ischemia. The increased production of protons due to metabolic modifications very quickly saturates the buffering capacity of the cell. Intracellular acidosis interferes directly and indirectly with the optimal functioning of the cell by increasing intracellular Na+ through the activation of Na+ /H+ exchangers and by Ca2+ activation of Na+ /Ca2+ exchangers, increasing the production of free radicals; changing the affinity of different proteins, such as enzymes and troponin C, to Ca2+; modifying terti‐ ary protein structures; inhibiting enzymes; and disrupting the function of sarcoplasmic pumps and carriers.[29]

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

opening of Na+ channels, delaying their inactivation.[29]-[31] The accumulation of amphiphilic compounds produces a time-

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

Moreover, the lactate/pyruvate ratio, intracellular acidosis and the absence of regenerated

volved in the initial step of glycolysis and prevent the optimal performance of anaerobic

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

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‐

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

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

Intracellular acidosis is a cardinal feature of cellular ischemia. The increased production of protons due to metabolic modifications very quickly saturates the buffering capacity of the cell. Intracellular acidosis interferes directly and indirectly with the optimal functioning of

the affinity of different proteins, such as enzymes and troponin C, to Ca2+; modifying terti‐ ary protein structures; inhibiting enzymes; and disrupting the function of sarcoplasmic

through the activation of Na+

/Ca2+ exchangers, increasing the production of free radicals; changing

tional properties of membrane proteins. Decreased activity of Na+

, affect the catalytic activity of the other enzymes in‐

, which are normally regenerated through oxi‐

/K+

/H+

exchangers and by


essential cofactors, such as NADH,H+

lack of the cofactors NADH,H+ and FAD+

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

gap-junction conductance. [31]

**4. Intracellular acidosis**

Ca2+ activation of Na+

pumps and carriers.[29]

the cell by increasing intracellular Na+

membrane.

**3.3. Metabolite detoxification pathways**

glycolysis. [23]

6 Artery Bypass

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; - : inhibition; + activation; H+: proton; e- : electron. **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+: proton; e- : electron.

**3.3. Metabolite detoxification pathways** 

The main source of protons during ischemia comes from the production of lactate from pyr‐ uvate by lactate dehydrogenase. The accumulation of extracellular lactate greatly reduces the effectiveness of the lactate/proton cotransporter, preventing the removal of protons. Ad‐ ditionally, the residual metabolic activity also contributes to acidosis, as the hydrolysis of an ATP molecule releases a proton.

citric acid cycle, but it also occupies a unique position in the cellular balance between life and death. Inhibition of the mitochondrial respiratory chain as a result of oxygen depriva‐

*inhibition Acceleration Acceleration Loss of membrane potential* 

H+

Without the respiratory chain oxidation-reduction reactions, proton accumulation in the mitochondrial intermembrane space is interrupted, disrupting the electrochemical gradient that allows ATP synthase to synthesize ATP. During ischemia, the protontranslocating F0F1-ATP synthase, which normally produces ATP, becomes an F0F1-ATPase and consumes ATP in order to pump protons from the matrix to the intermembrane space and maintain the mitochondrial membrane potential.[39],[40] The mitochondria

Without the respiratory chain oxidation-reduction reactions, proton accumulation in the mi‐ tochondrial intermembrane space is interrupted, disrupting the electrochemical gradient that allows ATP synthase to synthesize ATP. During ischemia, the proton-translocating F0F1-ATP synthase, which normally produces ATP, becomes an F0F1-ATPase and con‐ sumes ATP in order to pump protons from the matrix to the intermembrane space and maintain the mitochondrial membrane potential.[39],[40] The mitochondria therefore be‐

Free radical oxygen species (ROS) are highly reactive chemical compounds because they have unpaired electrons in their electron cloud. ROS are capable of oxidizing cellular con‐ stituents such as proteins, deoxyribonucleic acid (DNA), membrane phospholipids and oth‐ er adjacent biological structures. In addition to their role in ischemia, ROS are constitutively generated during metabolic processes and have an important role in cell signaling. Mito‐ chondrial respiration constitutively produces a small amount of ROS, primarily the superox‐

Anaerobic metabolism

**[Ca++]i**

*- protein degradation - Protein structure modifications*  -*Plasmic phospholipids degradation*  -*Mitochondrial dysfunction* 

Na+ <sup>m</sup>

Ca++

Ca++

Can.L

Impact of Ischemia on Cellular Metabolism http://dx.doi.org/10.5772/54509 9

Free radical oxygen species (ROS) are highly reactive chemical compounds because they have unpaired electrons in their electron cloud. ROS are capable of oxidizing cellular constituents such as proteins, deoxyribonucleic acid (DNA), membrane phospholipids and other adjacent biological structures. In addition to their role in ischemia, ROS are constitutively generated during metabolic processes and have an important role in cell signaling. Mitochondrial respiration constitutively produces a small amount of ROS, primarily the superoxide anion O2-● at complexes I and III of the electron transport chain. The anion is rapidly converted to hydrogen peroxide (H2O2) by metallo-enzymes and superoxide dismutase (SOD). [41]-[43] Cellular stress, particularly oxidative stress, dramatically increases mitochondrial ROS production by disrupting and later inhibiting oxidative phosphorylation. Moreover, the rise in mitochondrial calcium increases ROS production and greatly decreases the antioxidant capacity of mitochondria by

The mitochondrial calcium concentration is in equilibrium between its cytosolic concentration and the proton gradient on either side of the inner membrane of mitochondria. The loss of this gradient due to the inhibition of the respiratory chain, as well as the elevated cytosolic calcium that results from ischemia, allows for the accumulation of calcium in the mitochondria and promotes

Ischemic disturbances within mitochondria, such as calcium overload, loss of membrane potential, oxidative stress, mass production of free radicals, low NADPH/NADP+ and reduced glutathione to oxidized glutathione ratios (GSH/GSSG), low intramitochondrial concentration of ATP or high inorganic phosphate, will promote opening of the permeability transition pore (mPTP) upon reperfusion, a major player in I/R injury-mediated cell lethality.[42],[44] mPTP is a nonspecific channel, and its opening

tion is the cornerstone of metabolic disturbances.

*out*

*in*

ATP ADP+Pi

K+ Na+

↓O2

Figure 3. This figure summarizes the ionic perturbations in an ischemic cell.

**Figure 3.** This figure summarizes the ionic perturbations in an ischemic cell.

**[Na+ ATP ]i [H+]i**

Na+

× **Cellular edema** 

<sup>I</sup> <sup>I</sup> <sup>I</sup> <sup>V</sup>

therefore become a site of ATP consumption produced by anaerobic glycolysis.

come a site of ATP consumption produced by anaerobic glycolysis.

decreasing the glutathione peroxidase concentration and SOD activity.

mitochondrial swelling and the opening of the permeability transition pore.

**6.4. Opening of the mitochondrial permeability transition pore** 

**6.1. Disturbance of ATP synthesis.** 

**6.1. Disturbance of ATP synthesis.**

**6.2. An increase in free radical production** 

**6.2. An increase in free radical production**

**6.3. Intramitochondrial calcium overload** 
