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Apoptosis from Robbins second year flowchart

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Here is the complete Robbins apoptosis flowchart with both diagrams and full mechanistic breakdown:

Apoptosis - Robbins Pathology

Definition

Apoptosis is a programmed cell death pathway where cells activate intrinsic enzymes (caspases) that degrade their own nuclear DNA and cytoplasmic proteins. The cell breaks into membrane-bound apoptotic bodies that are rapidly phagocytosed - no inflammatory reaction is elicited.

The Two Pathways - Flowchart (Robbins Basic Pathology, Fig. 1.12)

Mechanisms of apoptosis - Robbins Basic Pathology Fig. 1.12

The More Detailed Version (Robbins & Cotran - Pathologic Basis of Disease, Fig. 2.16)

Mechanisms of apoptosis - Robbins Cotran Fig. 2.16 with APAF-1, FLIP, IAP

Step-by-Step Breakdown

MITOCHONDRIAL (INTRINSIC) PATHWAY

Triggers:
  • Growth factor withdrawal / absence of survival signal
  • DNA damage (radiation, toxins, free radicals)
  • Protein misfolding (ER stress)
Sequence:
  1. Stress activates BH3-only sensor proteins (BAD, BIM, BID, PUMA, NOXA)
  2. BH3-only proteins antagonize anti-apoptotic BCL-2 / BCL-XL (which normally keep mitochondrial outer membrane intact)
  3. Pro-apoptotic BAX / BAK are activated - they dimerize and insert into the outer mitochondrial membrane, forming channels
  4. Cytochrome c (+ other pro-apoptotic proteins like Smac/DIABLO) leaks from the intermembranous space into the cytosol
  5. Cytochrome c binds APAF-1 → forms the apoptosome (wheel-shaped complex)
  6. Apoptosome recruits and activates Caspase-9 (initiator caspase)
  7. Caspase-9 activates executioner caspases (Caspase-3, -6)
  8. IAPs (Inhibitors of Apoptosis Proteins) normally block executioner caspases - Smac/DIABLO neutralizes IAPs, releasing the brake
  9. → Nuclear fragmentation + breakdown of proteins and cytoskeleton → Apoptotic body formation

DEATH RECEPTOR (EXTRINSIC) PATHWAY

Triggers:
  • FasL binds Fas (CD95) on cell surface
  • TNF binds Type 1 TNF receptor
Sequence:
  1. Receptor cross-linking occurs
  2. Death domain on receptor recruits adaptor protein FADD (Fas-associated death domain)
  3. FADD recruits Pro-caspase-8 → forms the DISC (Death-Inducing Signaling Complex)
  4. FLIP (anti-apoptotic protein) can block this step by competing with Pro-caspase-8
  5. Pro-caspase-8 undergoes autocatalytic cleavage → active Caspase-8 (initiator caspase)
  6. Caspase-8 activates executioner caspases (Caspase-3, -6)
  7. → Same final execution phase as intrinsic pathway

BCL-2 Family Summary

GroupMembersFunction
Anti-apoptoticBCL-2, BCL-XL, MCL-1Keep outer mitochondrial membrane impermeable (4 BH domains: BH1-4)
Pro-apoptotic effectorsBAX, BAKForm channels in outer mitochondrial membrane (BH1-3)
BH3-only sensorsBAD, BIM, BID, PUMA, NOXASense cellular stress; activate BAX/BAK and inhibit BCL-2 (only BH3 domain)

Morphologic Features of Apoptosis (vs. Necrosis)

FeatureApoptosisNecrosis
Cell sizeShrinkageSwelling
NucleusChromatin condensation (pyknosis), fragmentationKaryolysis or karyorrhexis
MembraneIntact until lateEarly rupture
InflammationNoneYes
Apoptotic bodiesYes, rapidly phagocytosedNo
H&E appearanceRound, intensely eosinophilic mass with dense nuclear fragmentsGhost cells, loss of architecture

Causes Summary Table

ConditionMechanism
During embryogenesisLoss of growth factor signaling
Tissue turnover (gut epithelium, lymphocytes)Loss of survival signals
Hormone-dependent involution (endometrium, lactating breast)Reduced survival signals from hormone withdrawal
End of immune/inflammatory responseLoss of activation-induced survival signals
Self-reactive lymphocyte eliminationBoth intrinsic and extrinsic pathways
DNA damage (radiation, cytotoxic drugs)Activation of BH3-only proteins (p53-mediated)
Misfolded protein accumulationBH3-only protein activation; direct caspase activation
Viral infectionsViral proteins activate pro-apoptotic proteins; CTLs activate caspases
Sources: Robbins & Kumar Basic Pathology (9780323790185), p. 24-25 | Robbins, Cotran & Kumar Pathologic Basis of Disease (9780443264528), p. 56-60
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