Mechanisms of Cell Death Necrosis and Apoptosis

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FIGURE 14-33

Apoptosis and necrosis: two distinct morphologic forms of cell death. A, Necrosis. Cells undergoing necrosis become swollen and enlarged. The mitochondria become markedly abnormal. The main morphoplogic features of mitochondrial injury include swelling and flattening of the folds of the inner mitochondrial membrane (the christae). The cell plasma membrane loses its integrity and allows the escape of cytosolic contents including lyzoso-mal proteases that cause injury and inflammation of the surrounding tissues. B, Apoptosis. In contrast to necrosis, apoptosis is associated with a progressive decrease in cell size and maintenance of a functionally and structurally intact plasma membrane. The decrease in cell size is due to both a loss of cytosolic volume and a decrease in the size of the nucleus. The most characteristic and specific morphologic feature of apoptosis is condensation of nuclear chromatin. Initially the chromatin condenses against the nuclear membrane. Then the nuclear membrane disappears, and the condensed chromatin fragments into many pieces. The plasma membrane undergoes a process of "budding," which progresses to fragmentation of the cell itself. Multiple plasma membrane-bound fragments of condensed DNA called apoptotic bodies are formed as a result of cell fragmentation. The apoptotic cells and apoptotic bodies are rapidly phagocytosed by neighboring epithelial cells as well as professional phagocytes such as macrophages. The rapid phagocytosis of apoptotic bodies with intact plasma membranes ensures that apoptosis does not cause any surrounding inflammatory reaction.

Mitochondrion

Mitochondrial permeability transition

Positive feedback loop

Consequences of permeability transition: Disruption of Aym and mitochondrial biogenesis Breakdown of energy metabolism Uncoupling of respiratory chain Calcium release frommitochondrial matrix Hyperproduction of superoxide anion Depletion of glutathione

ROS Increase in ATP NAD/NADH effects [Ca2+]i „depletion depletion

ROS Increase in ATP NAD/NADH effects [Ca2+]i „depletion depletion

Disruption of anabolic reactions Dilatation of ER Activation of proteases Disruption of intracellular calcium compartimentalization Disorganization of cytoskeleton

Mitochondrial permeability transition

Positive feedback loop

Consequences of permeability transition: Disruption of Aym and mitochondrial biogenesis Breakdown of energy metabolism Uncoupling of respiratory chain Calcium release frommitochondrial matrix Hyperproduction of superoxide anion Depletion of glutathione

Tyrosin kinases G-proteins ?

Activation of endonucleases Activation of repair enzymes

(ATP depletion) Activation of poly(ADP) ribosly transferase (NAD depletion) Chromatinolysis, nucleolysis

Tyrosin kinases G-proteins ?

Disruption of anabolic reactions Dilatation of ER Activation of proteases Disruption of intracellular calcium compartimentalization Disorganization of cytoskeleton

Activation of endonucleases Activation of repair enzymes

(ATP depletion) Activation of poly(ADP) ribosly transferase (NAD depletion) Chromatinolysis, nucleolysis

FIGURE 14-34

Hypothetical schema of cellular events triggering apoptotic cell death. (From Kroemer et al. [25]; with permission.)

FIGURE 14-36

FIGURE 14-35

Phagocytosis of an apoptotic body by a renal tubular epithelial cell. Epithelial cells dying by apoptosis are not only phagocytosed by macrophages and leukocytes but by neighbouring epithelial cells as well. This electron micrograph shows a normal-looking epithelial cell containing an apoptotic body within a lyzosome. The nucleus of an epithelial cell that has ingested the apoptotic body is normal (white arrow). The wall of the lyzosome containing the apoptotic body (black arrow) is clearly visible. The apoptotic body consists of condensed chromatin surrounded by plasma membrane (black arrowheads).

DNA electrophoresis

Apoptic "ladder" pattern "

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Necrotic "smear" pattern

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DNA fragmentation in apoptosis vs necrosis. DNA is made up of nucleosomal units. Each nucleosome of DNA is about 200 base pairs in size and is surrounded by histones. Between nucleosomes are small stretches of DNA that are not surrounded by histones and are called linker regions. During apoptosis, early activation of endonuclease(s) causes double-strand breaks in DNA between nucleosomes. No fragmentation occurs in nucleosomes because the DNA is "protected" by the histones. Because of the size of nucleosomes, the DNA is fragmented during apoptosis into multiples of 200 base pair pieces (eg, 200, 400, 600, 800). When the DNA of apoptotic cells is electrophoresed, a characteristic ladder pattern is found.

In contrast, necrosis is associated with the early release of lyzosomal proteases, which cause proteolysis of nuclear histones, leaving "naked" stretches of DNA not protected by histones. Activation of endonucleases during necrosis therefore cause DNA cleavage at multiple sites into double- and single-stranded DNA fragments of varying size. Electrophoresis of DNA from necrotic cells results in a smear pattern.

Loss of survival factors Deficiency of renal growth factors (eg, IGF-1, EGF, HGF) Loss of cell-cell and cell-matrix interactions Receptor-mediated activators of apoptosis Tumor necrosis factor Fas/Fas ligand Cytotoxic events Ischemia; hypoxia; anoxia Oxidant injury Nitric oxide Cisplati

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