Apoptosis

Overview
  • Apoptosis is a unique morphological pattern of cell death which is coordinated by tightly regulated signaling pathways within dying cell. This highly regulated modality of cell death occurs in such a way that the dying cell's contents is neatly packaged into small packets which are rapidly taken up and degraded by local macrophages without the induction of inflammation.
Etiologies
  • Apoptosis is observed in a wide variety of physiological and pathological contexts throughout the body. Apoptosis occurs physiologically in cells which are no longer needed as occurs frequently during many developmental processes. Apoptosis occurs in pathological contexts when infected, neoplastic, or irreversibly injured cells essentially commit regulated suicide for the organism's overall benefit. See interlinks to this page for physiological and pathological contexts in which apoptosis occurs.
Molecular Pathogenesis
  • Overview
    • A wide variety of extrinsic and intrinsic molecular stimuli can induce apoptosis in a cell. All of these diverse stimuli are ultimately connected by different signaling pathways to a common final pathway which involves activation of Caspase proteins.
  • Extrinsic Stimuli
    • Apoptosis can be induced extrinsically by binding of ligand to certain apoptosis-inducing cellular membrane receptors. TNF-alpha binding to its receptor can induce Apoptosis in certain contexts. Cytotoxic, effector CD8+ T-cells can induce Apoptosis during Cell-mediated Immunity in infected cells by ligating Fas receptor on the target cell. Additionally, all cells require constant stimulation of certain receptors to remain alive and in the absence of such stimulation will undergo apoptosis. These receptors bind tissue-specific growth factors as well as components of the extracellular matrix thus guaranteeing that cells which exit their normal tissue environment automatically die, thus reducing the potential for metastasis.
  • Intrinsic Stimuli
    • Of the variety of stimuli which induce apoptosis within a cell, perhaps the most potent is damage to a cell's genome. Consequently, if sufficient DNA damage occurs, a cell will automatically activate apoptotic pathways.
  • Caspase Activation
    • Caspases are a family of proteases which are normally held inactive in the cytosol. Upon activation, Caspases degrade a wide variety of cellular proteins which ultimately result in cell death. Caspases also activate nucleases which completely degrade the cell's genome into small, discrete fragments. Once initiated by caspases, the apoptotic program results in degradation of cellular material and its packaging into small units which begin blebbing from the plasma membrane. In the end, the cell transforms into a constellation of small membrane-bound units containing degraded cellular debris which are rapidly phagocytosed by local tissue macrophages.
  • Caspase Regulation
    • Given the highly destructive role of Caspases, it is not surprising that the activity of these proteins is tightly regulated. One of the prime regulators of caspase activation is Cytochrome C, a component of the mitochondrial inner membrane which is released in response to a variety of pro-apoptotic stimuli. Consequently, control of Cytochrome C release is itself a major regulatory point of apoptosis
    • Proteins such as BCL-2 and BCL-XL inhibit apoptosis by stabilizing Cytochrome C within the Mitochondria while proteins such as BAD and BAX promote apoptosis by promoting cytosolic release of Cytochrome C.
Morphology
  • As cells undergo apoptosis they generally shrink in size and their nuclear chromatin begins to condense and fragment (Karryohexis). As apoptosis continues, small blebs begin to form at the plasma membrane and eventually the entire cell disintegrates into small membrane-bound packages which include degraded cellular proteins, nucleic acids, and pieces of organelles. One of the most important features of apoptosis is the non-inflammatory nature of these membrane-bound vesicles which are taken up by local tissue macrophages without any inflammatory reaction. Because of this lack of inflammation, cells which undergo apoptosis are often easy to miss in histological analysis.