**7. Structural and functional modifications**

The cytoskeleton, the internal structural organization of a cell, is composed of a highly regu‐ lated complex network of organized structural proteins, including actin, microtubules and lamins. The cytoskeleton performs multiple functions. It maintains internal cellular com‐ partmentalization and mediates the transmission of mechanical forces within the cell to ad‐ jacent cells and the extracellular matrix, the distribution of organelles, the movement of molecules or components and the docking of proteins such as membrane receptors or ion channels. Ischemia deconstructs the cytoskeleton. [53]-[56] The high intracellular concentra‐ tions of Ca2+ that are associated with ischemia activate multiple phosphorylases and proteas‐ es that disassemble and degrade the cytoskeleton, thereby eliminating the functions that rely on its integrity, such as phagocytosis, exocytosis, myofilament contraction, intercellular communication and cell anchorage. Destruction of the internal architecture worsens I/R inju‐ ries and leads to apoptosis. [53],[56],[57] During ischemia, all elements of the cytoskeleton are affected, but with different kinetics.[54],[55] Moreover, the accumulation of osmotically active particles, including lactate, sodium, inorganic phosphate and creatine, induces cellu‐ lar oedema.[38]

ide anion O2

10 Artery Bypass

transition pore.

tration and SOD activity.

**6.3. Intramitochondrial calcium overload**

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


converted to hydrogen peroxide (H2O2) by metallo-enzymes and superoxide dismutase (SOD). [41]-[43] Cellular stress, particularly oxidative stress, dramatically increases mito‐ chondrial 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 decreasing the glutathione peroxidase concen‐

The mitochondrial calcium concentration is in equilibrium between its cytosolic concentra‐ tion 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 cytosol‐ ic calcium that results from ischemia, allows for the accumulation of calcium in the mito‐ chondria and promotes mitochondrial swelling and the opening of the permeability

Ischemic disturbances within mitochondria, such as calcium overload, loss of membrane po‐

glutathione to oxidized glutathione ratios (GSH/GSSG), low intra-mitochondrial concentra‐ tion of ATP or high inorganic phosphate, will promote opening of the permeability transi‐ tion pore (mPTP) upon reperfusion, a major player in I/R injury-mediated cell lethality.[42], [44] mPTP is a nonspecific channel, and its opening suddenly increases the permeability of the inner mitochondrial membrane to both water and various molecules of high molecular weight (> 1,500 kDa). The opening of mPTPs abolishes the mitochondrial membrane poten‐ tial and uncouples oxidative phosphorylation, which empties the mitochondria of its matrix and induces apoptosis by releasing the intra-mitochondrial proteins cytochrome c, endonu‐

The cytoskeleton, the internal structural organization of a cell, is composed of a highly regu‐ lated complex network of organized structural proteins, including actin, microtubules and lamins. The cytoskeleton performs multiple functions. It maintains internal cellular com‐ partmentalization and mediates the transmission of mechanical forces within the cell to ad‐ jacent cells and the extracellular matrix, the distribution of organelles, the movement of molecules or components and the docking of proteins such as membrane receptors or ion channels. Ischemia deconstructs the cytoskeleton. [53]-[56] The high intracellular concentra‐ tions of Ca2+ that are associated with ischemia activate multiple phosphorylases and proteas‐ es that disassemble and degrade the cytoskeleton, thereby eliminating the functions that rely on its integrity, such as phagocytosis, exocytosis, myofilament contraction, intercellular

and reduced

tential, oxidative stress, mass production of free radicals, low NADPH/NADP+

clease G, Smac/Diablo and apoptosis-inducing factor into the cytosol. [44]-[52]

**7. Structural and functional modifications**

Regulatory cellular mechanisms provide intracellular homeostasis that enables optimal en‐ zyme function in a relatively narrow range of environmental conditions. The conditions cre‐ ated by ischemia, such as acidosis and calcium overload, modify or inhibit the activity of many enzymes due to changes in the pH and tertiary structures, affecting cellular metabo‐ lism. For example, ischemia induces the conversion of xanthine dehydrogenase to xanthine oxidase.[36]-[38] These two enzymes catalyze the same reactions, converting hypoxanthine to xanthine and xanthine to uric acid. The first reaction uses NAD+ as a cofactor, whereas the second uses oxygen and produces O2 -●, a free radical.
