Tissue Homeostasis Cell Death

Apoptosis

A controlled, programmed form of cell death in which the cell dismantles itself without inflammation; contents are packaged into apoptotic bodies.

Necrosis

Uncontrolled cell death caused by injury; cells swell, burst, and leak contents, triggering inflammation.

Purpose of apoptosis

Eliminates damaged, dangerous, or unnecessary cells to protect the organism.

Developmental role of apoptosis

Used to sculpt fingers and toes by removing interdigital cells; removes embryonic tail structures.

BCL2 family location

Proteins located in the outer mitochondrial membrane that regulate intrinsic apoptosis.

BAX

Pro-apoptotic protein that forms pores in the mitochondrial outer membrane to promote apoptosis.

BAK

Pro-apoptotic protein that oligomerizes with BAX to form mitochondrial pores.

BCL2

Anti-apoptotic protein that prevents BAX and BAK activation, blocking cytochrome c release.

Balance between BCL2 proteins

Cell survival or death depends on the ratio of anti-apoptotic (BCL2) to pro-apoptotic (BAX/BAK) proteins.

DNA damage effect on BCL2 family

DNA damage activates p53, which increases transcription of PUMA and NOXA to activate BAX and BAK.

Intrinsic apoptosis trigger

Initiated by internal stress such as DNA damage, ER stress, or loss of survival factors.

Mitochondria role in apoptosis

Act as the control center; release cytochrome c to activate the caspase cascade.

BAX BAK activation

Oligomerize in the mitochondrial outer membrane in response to apoptotic signals.

Mitochondrial pore

The BAX/BAK oligomeric pore that allows cytochrome c to escape.

Cytochrome c normal location

Stored in the mitochondrial intermembrane space as part of the electron transport chain.

Cytochrome c release

Key irreversible step of intrinsic apoptosis allowing apoptosome formation.

Adaptor protein binding

Cytochrome c binds Apaf-1 in the cytosol.

Apoptosome

A heptameric complex of Apaf-1 and cytochrome c that activates initiator procaspase-9.

Apoptosome function

Recruits and activates caspase-9, triggering the caspase cascade.

Initiator caspase activation

Procaspase-9 is cleaved to active caspase-9 by the apoptosome.

Executioner caspase activation

Caspase-9 activates executioner caspases like caspase-3.

Caspase cascade

Irreversible proteolytic chain that dismantles the cell.

Mitochondrial commitment step

Cytochrome c release commits the cell to apoptosis.

Effects on mitochondrial integrity

BAX/BAK pores disrupt the mitochondrial membrane potential.

ATP level during early apoptosis

ATP remains fairly preserved to allow controlled dismantling.

Mitochondria as apoptosis timer

Once cytochrome c is released, the cell cannot stop apoptosis.

Intrinsic pathway overview

Starts with internal stress → activates BAX/BAK → cytochrome c release → apoptosome → caspases.

p53 role in intrinsic apoptosis

Activates transcription of pro-apoptotic proteins such as PUMA and NOXA.

Loss of survival factors

Increases activity of pro-apoptotic proteins and activates intrinsic apoptosis.

Apoptotic threshold

Determined by balance between BCL2 and BAX/BAK proteins.

Irreversibility of intrinsic apoptosis

Once cytochrome c leaves mitochondria, apoptosis cannot be reversed.

Extrinsic apoptosis

Triggered by extracellular ligands binding to death receptors.

Death receptors

Receptors such as FAS that initiate apoptotic signaling when activated.

FAS FASL system

Used by cytotoxic T cells to kill infected or cancerous cells.

DISC complex

Death-inducing signaling complex that activates caspase-8.

Caspase 8

Initiator caspase of the extrinsic pathway.

Extrinsic to intrinsic crosstalk

Caspase-8 can cleave BID into tBID, which activates mitochondrial apoptosis.

Caspases

Proteases that cleave proteins after aspartate residues; execute apoptosis.

Initiator caspases

Activated first (caspase-8 extrinsic, caspase-9 intrinsic).

Executioner caspases

Caspase-3, -6, -7; cleave structural and nuclear proteins to dismantle the cell.

Procaspases

Inactive precursors that require cleavage for activation.

Proteolytic cascade

Self-amplifying chain of caspase activation that is irreversible.

Apoptotic bodies

Membrane-bound blebs containing cellular contents.

No inflammation

Because the membrane stays intact and phagocytes clear contents before leakage.

Phosphatidylserine exposure

“Eat me” signal flipped to outer membrane leaflet to attract phagocytes.

Phagocyte recognition

Macrophages detect phosphatidylserine and engulf apoptotic bodies.

Point of no return in apoptosis

Release of cytochrome c from mitochondria.

Difference between necrosis and apoptosis

Necrosis is uncontrolled and inflammatory; apoptosis is controlled and non-inflammatory.

Why mitochondria are central

They decide when apoptosis is irreversibly triggered.

Role of p53 in apoptosis

Drives expression of pro-apoptotic genes; if mutated, apoptosis fails and cancer develops.

Cancer and apoptosis failure

Loss of apoptosis (e.g., BCL2 overexpression or p53 mutation) allows damaged cells to survive → tumors form