Cell Death: Apoptosis and Necrosis

Cell Death: Apoptosis and Necrosis

• Cell death is a fundamental process of life, playing a crucial role in embryonic development, maintaining homeostasis, and eliminating damaged cells.

Apoptosis

• Apoptosis is a programmed cell death, driven by tightly regulated intracellular signal transduction pathways.
• It occurs under normal physiological conditions, and the cell is an active participant in its own demise, also known as "cellular suicide".
• Characteristics of apoptosis include:
  • Cell shrinkage
  • Membrane blebbing
  • Positional organelle loss
  • DNA condensation and fragmentation
• Apoptosis is beneficial and important in:
  • Embryonic development (e.g., digit formation)
  • Adults (e.g., normal cell turnover, tissue homeostasis, immune tolerance, and nervous system development)
  • Eliminating damaged, abnormal, or activated cells

Physiological Conditions of Apoptosis

• Embryonic development: helps in digit formation, and lack of apoptosis can lead to syndactyly (webbed fingers).
• Adults:
  • Normal cell turnover
  • Tissue homeostasis
  • Induction and maintenance of immune tolerance
  • Development of the nervous system
  • Endocrine-dependent tissue atrophy
  • Elimination of activated, damaged, and abnormal cells

Apoptosis in Pathologic Conditions

• DNA damage due to radiation, chemotherapy
• Accumulation of misfolded proteins leading to ER stress and apoptosis
• Cell death in viral infections (e.g., HIV, Adenovirus) or by the host immune response (e.g., hepatitis)
• Organ atrophy after duct obstruction

Apoptosis Pathways

• Extrinsic pathway (death receptor-mediated events)
• Intrinsic pathway (mitochondria-mediated events)

Extrinsic Pathway

• "Death receptors" are members of the tumor necrosis factor (TNF) receptor superfamily.
• Death receptors have a cytoplasmic domain called the "death domain", which plays a critical role in transmitting the death signal.
• At least 14 different members of caspases in mammalian cells have been identified, categorized into:
  • Signaling or Initiator caspases
  • Effector or Executioner caspases
  • Inflammatory caspases

Intrinsic Pathway

• Stimuli that initiate the intrinsic pathway produce intracellular signals, such as radiation (DNA damage) and absence of certain growth factors, hormones, and cytokines.
• These stimuli cause changes in mitochondrial outer membrane permeabilization (MOMP), leading to the release of pro-apoptotic proteins (e.g., cytochrome c, Smac/DIABLO, AIF, endonuclease G, and CAD) from the inter-membrane space into the cytosol.
• The Bcl-2 family of proteins regulates the control and regulation of apoptotic mitochondrial events.

Biochemical Features of Apoptosis

• Protein cleavage occurs via activation of several members of the cysteine protease family (caspases).
• Activation of endonucleases leads to DNA breakdown into 50-300 kb pieces.
• Phagocytic recognition is facilitated by the expression of phosphatidylserine in the outer layer of the membrane.

Morphological Features of Apoptosis

• Cells shrink and round up.
• Cells become more dense and detach from neighbors.
• Chromatin becomes very dense and separates into homogeneous masses.
• Cells undergo budding and blebbing, forming apoptotic bodies, which are then removed by phagocytosis.

Necrosis

• Necrosis is death of cells and tissues in the living animal, stimulated by external factors such as infection, toxins, and physical injury.
• It is characterized by cytoplasmic swelling, denaturation of intracellular proteins, and enzymatic digestion.
• Necrotic cells are unable to maintain membrane integrity, leading to the release of cellular contents, which may elicit inflammation in the surrounding tissue.
• General causes of necrosis include:
  • Poisons and toxins
  • Chemical injuries (e.g., strong acids, alkalies)
  • Circulatory disturbances (e.g., anemia, congestion, ischemia)
  • Mechanical injuries (e.g., cutting, crushing, rubbing)
  • Physical injuries (e.g., extreme temperature, electricity, free radicals)