Apoptosis

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Apoptosis

• Dr. Ed Smith
• Office 2119
• Phone X1764

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Apoptosis

• Programmed cell death (apoptosis), functions to
  eliminate unwanted cells with minimal local
  disturbance. The cell membrane remains intact
  but the process renders it a target for
  phagocytosis with out eliciting an inflammatory
  reaction (unlike necrosis).
• Apoptosis necrosis may be concurrent and share
  some common features and mechanisms.

• Fig 1-26 p 28

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Apoptosis
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Apoptosis

• Controlled demolition involves disrupting the
  integrity of a few key components that results in
  catastrophic failure with minimal collateral
  damage

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Causes of Apoptosis

• Physiologic Causes
• Developmental
• Hormone dependent involution of tissues
• Cell deletion from proliferating cell populations
  to maintain a particular cell number
• Death of cells that have completed their function
  (PMNs after the infection).
• Deletion of potentially self-reactive lymphocytes
• Cell death induced by Cytotoxic T-cells (virally
  infected cells and tumor cells)

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Causes of Apoptosis

• Pathologic causes
• Cell death by a variety of injuries
• Irreparable DNA damage
• Extensive damage beyond normal repair mechanisms
• Sublethal damage in cells with impaired repair
  mechanism
• Induction of MPT (leaky mitochondria)
• Some minor insults ( heat, hypoxia)
• Cell death in certain viral infections
• Cell death in tumors ()

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Apoptosis

• Morphologic features of apoptosis vs. necrosis

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Apoptosis
Fig 1-9 p 13
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Apoptosis

• Biochemical Features of Apoptosis
• Protein cleavage by capasas ( a protease family)
  they activate DNAses
• Internucleosomal cleavage of DNA into 200 base
  pair fragments
• Plasma membrane alterations (membrane flipping)
  that allow phagocytosis of apoptotic cells.

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• Fig 1-28 p 29

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Mechanisms of Apoptosis

• Apoptosis may start in a number of ways but
  culminates in the activation of capases, it can
  be divided into two phases
• initiation (capase activation)
• execution (enzymatic cell death).

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Mechanisms of Apoptosis

• Initiation phase two possible mechanisms
• Extrinsic (Death Receptor) pathway
• Death receptors are receptors for tumor necrosis
  factor (TNF). When a number of these receptors
  bind TNF they cross-link and activate a capase
  molecule which initiates a capase activation
  cascade.
• Intrinsic (Mitochondrial) Pathway
• Mitochondrial permeability is influenced by a
  ratio by pro-apoptotic and anti-apoptotic
  molecules cells lacking trophic signals or
  experiencing stress have decreased levels of
  anti-apoptotic molecules and increased levels of
  pro-apoptotic molecules. This results in leakage
  of capase activating proteins from the
  mitochondria. The balance between these opposing
  molecules controls mitochondrial permeability

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Mechanisms of Apoptosis

• Execution Pathway
• Capases produced in the initiation phase
  (initiation- capases) activate a second set of
  capases (executioner- capases) which are directly
  responsible for wholesale intracellular
  destruction.
• Executioner capases
• Cleave cytoskeltal elements
• Nuclear matrix proteins
• In the nucleus capases cleave proteins involved
  in
• DNA replication
• DNA repair

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Examples of Apoptosis

• Growth factor deprivation (intrinsic pathway)
• DNA damage triggers apoptosis by p53 accumulation
  (mutated p53 in some cancers)
• TNF receptor activation, important in
  inflammation and elimination of self-directed
  lymphocytes (auto immune diseases)
• Cytotoxic T lymphocytes recognize foreign
  antigens on infected cells and directly initiate
  the execution phase of apoptosis

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Dysregulated Apoptosis (too much or too little)

• Too little apoptosis increased cell survival
• Cancer
• Autoimmune disorders
• Developmental defects
• Too much excessive cell death
• Neurodegenerative diseases with the loss of
  specific sets of neurons
• Ischemic injury
• Death of virally infected cells.
• Disorders of rapid cell aging

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The amazing thing is that it goes right so many
more times than it goes wrong!
Day 30
Day 41
Day 46
Day 36
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Apoptosis

• Approximately one in 2,000 to 2,500 live births
• Most commonly the second and third toes are
  webbed or joined by skin and flexible tissue.
• Dan Aykroyd Canada, actor1
• Marge Simpson - United States, cartoon character
  (mentioned in her trial for shoplifting)
• Joseph Stalin (Unproven) Soviet Union, General
  Secretary of the Communist Party of the Soviet
  Union

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Conclusions

• Apoptosis is an orchestrated self directed
  destruction of the cell
• There is little or no initiation of inflammation
  (vs. necrosis)
• Physiologic pathologic causes
• Developmental
• Unneeded cells
• Cells identified as dangerous
• Damaged cells especially damaged DNA or leaky
  mitochondria
• Morphologic features
• Shrunken cell
• Precise DNA cleavage
• Membrane intact
• No inflammation

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Conclusion

• Biochemical features of apoptosis
• Capase activation
• Specific DNA cleavage pattern
• Cell membrane alteration that promote
  phagocytosis
• Mechanism of apoptosis
• Initiation phase (capase activation)
• Extrinsic (death receptor) pathway
• Intrinsic (mitochondrial) pathway
• Execution pathway activation of executioner
  capases
• Examples of apoptosis
• Physiologic
• Pathologic
• Dysregulated Apoptosis
• Too little
• Too much

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• Experts at the Heidelberg University library said
  notes scribbled in the margins of a book by its
  owner in October 1503 confirm -- once and for all
  -- that the model for the painting was Lisa del
  Giocondo, the wife of a wealthy 16th century
  Florentine merchant.