Cell Death

General Course Disclaimer

  • This course may contain graphic images that some students may find disturbing.

Overview of Cell Death (Chapter 18)

  • Key Questions:

    • How do cells die?

    • What is pre-programmed cell death?

    • How is cell death regulated?

    • Connection between cell survival signaling and diseases.

Two Types of Cell Death

  1. Apoptosis

    • Programmed cell death (Greek: "falling off")

    • Characterized by:

      • Phagocytosis of apoptotic cells

      • Enzymatic digestion of cell fragments

  2. Necrosis

    • Non-programmed cell death (Greek: "state of death")

Apoptosis - A Basic Biological Phenomenon

  • Defined by J.F.R. Kerr et al. (1972):

    • Mechanism of controlled cell deletion.

    • Plays an opposite role to mitosis in regulating animal cell populations.

    • Features: nuclear and cytoplasmic condensation, formation of apoptotic bodies.

    • Phagocytosis: Apoptotic bodies are taken up by other cells and degraded by lysosomal enzymes.

    • Involved in:

      • Cell turnover in healthy tissues

      • Embryonic development

      • Response to therapeutic agents.

Importance of Apoptosis

  • Essential for:

    • Creation and maintenance of limbs and organs.

    • Elimination of damaged/abnormal cells:

      • Irreparable organelle damage.

      • Irreparable DNA damage.

      • Response to infections and cancer.

Biochemical Markers of Apoptosis

  • Key markers include:

    • DNA cleavage.

    • Phosphatidylserine (PS) exposure on cell surfaces ("eat me" signal).

    • Leakage of mitochondrial contents.

    • Inactivation of "don't eat me" signals.

Mechanism of Caspases in Apoptosis

  • Caspases:

    • Intracellular proteases that initiate apoptosis.

    • Require cysteine in their active site; cleave proteins at aspartate residues.

Classifications of Caspases

  1. Initiator Caspases:

    • Trigger apoptosis.

  2. Executioner Caspases:

    • Act on target molecules (over 1000).

    • Both types exist as inactive precursors (procaspases).

Apoptosis Signaling Pathways

  1. Extrinsic Pathway:

    • Activated by cell surface death receptors (e.g., TNF family).

  2. Intrinsic Pathway:

    • Activated from within the cell in response to stress (e.g., DNA damage).

    • Involves mitochondrial release of cytochrome C.

Regulation by Bcl2 Family Proteins

  • Regulate the intrinsic pathway:

    • Control release of cytochrome C and other mitochondrial proteins.

    • Three classes based on hydrophobic domain structure.

Role of p53 in Apoptosis

  • DNA damage stimulates:

    • p53 to activate transcription of BH3-only genes.

    • Involvement of various checkpoint kinases (ATM, ATR, checkpoint kinase 1&2).

Inhibition of Apoptosis

  • Extracellular survival factors inhibit apoptosis by:

    1. Increasing anti-apoptotic Bcl2 family proteins.

    2. Inactivating BH3-only proteins.

    3. Modulating proteins involved in caspase regulation.

Consequences of Dysregulated Apoptosis

  • Too much apoptosis:

    • Leads to conditions such as heart attacks and strokes.

  • Too little apoptosis:

    • Results in excessive cell numbers and cancers.

    • Cancer cells often evade apoptosis through various mutations.

  • Key mutations:

    • In Bcl2 family proteins.

    • In p53, preventing cell cycle arrest and apoptosis in response to DNA damage.

Diseases Related to Apoptosis

  • Apoptosis imbalance is linked to diseases such as:

    • Cancer.

    • Autoimmune disorders (due to excessive lymphocyte counts).

    • Various tissue and organ degenerative conditions.