Introduction to apoptosis - A brief overview of the mechanisms of apoptosis
Apoptosis or programmed cell death is defined as "a mechanism of cellular suicide which occurs after sufficient cellular damage".
Apoptosis is first characterized by a change in the refractive index of the cell followed by cytoplasmic shrinkage and nuclear condensation. The cell membrane begins to show blebs and eventually these blebs separate from the dying cell and form "apoptotic bodies". Apoptotic cells also cease to maintain phospholipid asymmetry in the cell membrane, and phosphotidylserine appears on the outer leaflet. The mitochondrial outer membrane also undergoes changes that include loss of its electrochemical gradient, and substances like cytochrome c leak into the cytoplasm. Finally, adjacent cells or macrophages phagocytose apoptotic bodies and the dying cell. The apoptotic cell does not provoke an inflammatory response, and only individual cells are affectedby apoptosis in vivo.
The alternative mitochondrial pathway (intrinsic pathway) can be activated by events such as DNA damage. Themitochondrial pathway involves members of the Bcl-2 family that regulate cytochrome c release from the mitochondria. Expression of phagocytic recognition molecules at the surface of apoptotic cells may lead at anystage to their removal from the tissue. One of the earliest changes in apoptosis is the movement of negatively charged phospholipids molecules (phosphotidylserine) from the inside of the cell membrane to the outside.
Annexin-V labelling of phosphotidylserine exposure is an established procedure for identifying cells at an earlier stage in apoptosis.
View our apoptosis pathway diagram for further details.
Apoptosis is first characterized by a change in the refractive index of the cell followed by cytoplasmic shrinkage and nuclear condensation. The cell membrane begins to show blebs and eventually these blebs separate from the dying cell and form "apoptotic bodies". Apoptotic cells also cease to maintain phospholipid asymmetry in the cell membrane, and phosphotidylserine appears on the outer leaflet. The mitochondrial outer membrane also undergoes changes that include loss of its electrochemical gradient, and substances like cytochrome c leak into the cytoplasm. Finally, adjacent cells or macrophages phagocytose apoptotic bodies and the dying cell. The apoptotic cell does not provoke an inflammatory response, and only individual cells are affectedby apoptosis in vivo.
The mechanisms of apoptosis
Apoptosis can be induced in response to many external stimuli (extrinsic pathway) including activation of cell surface receptors such as Fas, TNFR1 (tumor necrosis factor receptor 1), TRAIL-R1 (TNF-related apoptosis inducing ligand receptor 1), TRAIL-R2, p75-NGFR (p75-nerve growth factor receptor) and others. These "death receptors" have two distinct signaling motifs: death domains (DD) and death effector domains (DED) that allow them to interact with other proteins involved in the apoptosis cascade. Typically the extrinsic pathway involves activating the initiator caspase, caspase-8, which in turn either activates caspase-3 or cleaves the Bcl-2 family member, Bid, leading to the formation of the apoptosome and activation of caspase-9.The alternative mitochondrial pathway (intrinsic pathway) can be activated by events such as DNA damage. Themitochondrial pathway involves members of the Bcl-2 family that regulate cytochrome c release from the mitochondria. Expression of phagocytic recognition molecules at the surface of apoptotic cells may lead at anystage to their removal from the tissue. One of the earliest changes in apoptosis is the movement of negatively charged phospholipids molecules (phosphotidylserine) from the inside of the cell membrane to the outside.
Annexin-V labelling of phosphotidylserine exposure is an established procedure for identifying cells at an earlier stage in apoptosis.
View our apoptosis pathway diagram for further details.
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