STEPTRACKERGENERAL PRINCIPLES | PATHOLOGY + CELL BIOLOGY | HIGH-YIELD REVIEW

Apoptosis

ATP-dependent, programmed death of single cells — tidy, silent, and without inflammation.

FOCUS ON
Know the two doorways into the same caspase cascade. The intrinsic pathway runs through mitochondria, with BCL-2 as the guard. The extrinsic pathway runs through Fas, TNF receptors and cytotoxic T cells. Then link each defect to its disease: follicular lymphoma, ALPS, cancer from p53 loss.
COMPONENT
HOW IT WORKS
KEY MOLECULES
DISEASE / EXAMPLE
Morphology
what you see
Cell shrinks, cytoplasm turns intensely eosinophilic, nucleus condenses (pyknosis) and fragments (karyorrhexis). Membrane blebs into apoptotic bodies that macrophages eat.
Membrane stays intact → no inflammation
Councilman bodies in viral hepatitis
Execution phase
common endpoint
Executioner caspases activate proteases that dismantle the cytoskeleton and endonucleases that cut DNA.
Caspases 3, 6, 7 · DNA ladder (~180-bp fragments) · phosphatidylserine flips outward ("eat me")
Annexin V binds exposed phosphatidylserine
Intrinsic pathway
mitochondrial
DNA damage, growth-factor or hormone withdrawal, or stress → p53 rises → BAX/BAK form pores in the outer membrane → cytochrome c leaks out → apoptosome → caspase-9.
Anti-apoptotic: BCL-2, BCL-xL · Pro-apoptotic: BAX, BAK, BIM
BCL-2 overexpression, t(14;18) → follicular lymphoma
Extrinsic — death receptor
ligand-triggered
FasL binds Fas (CD95) or TNF binds TNFR1 → adaptor (FADD) → caspase-8.
Fas, FasL, TNF, FADD, caspase-8
Thymic negative selection; Fas defect → autoimmune lymphoproliferative syndrome (ALPS)
Extrinsic — CTL / NK cell
immune killing
Perforin punches pores, then granzyme B enters and activates caspases directly.
Perforin, granzyme B
Killing of virus-infected and tumor cells; graft rejection
Physiologic apoptosis
normal life
Shapes and trims tissues: embryogenesis, hormone withdrawal, removal of used immune cells.
Hormone loss → intrinsic pathway
Interdigital webs (failure → syndactyly), endometrial shedding, thymic involution
Pathologic apoptosis
disease
Irreparable DNA damage, viral infection, misfolded proteins, duct obstruction.
p53-driven intrinsic pathway; CTL attack
Radiation and chemotherapy injury, viral hepatitis, neurodegeneration, atrophy after obstruction

Mechanism — two doors, one cascade

IntrinsicDNA damage / no growth factor
→
p53 ↑, BCL-2 ↓BAX/BAK pores
→
Cytochrome c outApoptosome → caspase-9
→
Caspase-3, 6, 7Proteases + endonucleases
ExtrinsicFasL or TNF binds receptor
→
FADDAdaptor recruits
→
Caspase-8Initiator
→
Caspase-3, 6, 7Same executioners

CTLs bypass receptors: perforin + granzyme B activate the executioner caspases directly.

Apoptosis vs necrosis

FEATURE
APOPTOSIS
NECROSIS
Extent
Single cells
Groups of cells
Energy
ATP required
ATP not required
Cell size
Shrinks
Swells
Membrane
Intact, blebs
Ruptured, contents leak
Inflammation
None
Always
DNA
Orderly ladder
Random smear
Setting
Physiologic or pathologic
Always pathologic

How it's tested

COMMON CONFUSIONPyknosis and karyorrhexis appear in both forms of death. What separates them is single cells, an intact membrane and no inflammation.
THE TRAPFollicular lymphoma is asked as "mechanism of tumor growth." The answer is reduced apoptosis from BCL-2 overexpression, not faster proliferation.
YOUR APPROACHDamage from inside the cell points to the intrinsic (mitochondrial) pathway. A signal from outside or an immune cell points to the extrinsic pathway or perforin/granzyme. Then name the guard or trigger molecule.

If you see… think…

Pink round globules in hepatocytes in viral hepatitis → Councilman bodies (apoptosis)
t(14;18) in a nodular lymphoma → BCL-2 overexpression
Webbed fingers at birth → failed interdigital apoptosis
Child with big nodes, spleen and autoimmune cytopenias → Fas defect (ALPS)
CTL killing a virus-infected cell → perforin + granzyme B
Annexin V–positive cells on flow → phosphatidylserine flip (early apoptosis)
DNA ladder on gel electrophoresis → endonuclease activity
Cells with DNA damage that keep dividing → TP53 loss
Menstrual shedding → apoptosis from hormone withdrawal