Apoptosis: Mechanisms, Causes, and Morphological Features

Apoptosis

“A pattern of cell death in which cells activate enzymes that degrade the cell's own nuclear DNA and nuclear and cytoplasmic proteins.”

Causes

I. Physiologic (Most Common)

• Programmed destruction of cells during embryogenesis.
• Hormone-dependent involution of tissues in the adult (e.g., endometrium).
• Cell loss in proliferating cell populations, such as epithelial cells in intestinal crypts.
• Death of host cells after serving their useful purpose (e.g., neutrophils in an acute inflammatory response).

II. Pathologic

• DNA damage due to radiation, cytotoxic drugs, and hypoxia.
• Accumulation of misfolded proteins causing endoplasmic reticulum (ER) stress (e.g., degenerative diseases of the CNS).
• Cell death associated with viral infections, such as HIV or adenovirus.
• Pathologic atrophy of the pancreas or parotid gland after duct obstruction.

Mechanisms

Apoptosis occurs in two distinct phases: the initiation phase and the execution phase.

I. Initiation Phase

Activation of enzymes known as caspases occurs via two distinct pathways:

A. Intrinsic (Mitochondrial) Pathway

This is the major pathway. Activation of sensors of cellular stress and damage (BAD, BIM, and BID) causes antagonism of anti-apoptotic molecules (BCL-2) and activation of pro-apoptotic molecules (BAX and BAK). This results in increased permeability of the outer mitochondrial membrane, leading to the release of cytochrome c into the cytoplasm, which activates initiator caspases (caspase-9).

B. Extrinsic (Death-Receptor Initiated) Pathway

Cross-linking of plasma membrane death receptors—specifically Type 1 TNF receptor and Fas—by external ligands such as TNF and Fas ligand (FasL) results in the activation of initiator caspases (caspase-8 and caspase-10).

II. Execution Phase

Initiator caspases trigger the activation of executioner caspases (caspase-3 and caspase-6), which cause the disruption of the cytoskeleton and fragmentation of the nucleus.

Morphology

1. The cell becomes smaller with dense cytoplasm and tightly packed organelles.
2. Peripheral aggregation of chromatin occurs under the nuclear membrane into dense masses.
3. The nucleus breaks into two or more fragments.
4. Surface blebbing occurs, followed by fragmentation into membrane-bound apoptotic bodies.
5. The plasma membrane remains intact with an altered structure.
6. Phagocytosis of apoptotic cells or cell bodies is performed by macrophages.
7. There is no associated inflammatory response.

Necrosis vs. Apoptosis

Other Mechanisms of Cell Death

Additional forms of cell death include necroptosis, pyroptosis, and ferroptosis.