cell death

CELL DEATH

Cell death is a normal and necessary biological process that occurs during embryonic development, fetal maturation, tissue remodeling, maintenance of normal cell populations, and response to severe injury.

MAJOR MECHANISMS OF CELL DEATH

The module describes apoptosis, oncotic necrosis, and regulated necrosis, including necroptosis and MPT-driven necrosis.

APOPTOSIS

A regulated form of cell death in which an individual cell actively dismantles itself.

NECROSIS

An enzyme-driven sequence of morphological changes following irreversible cell death in living tissue.

ONCOTIC NECROSIS

A passive, uncontrolled and inflammatory form of cell death associated with severe injury, cellular swelling, membrane rupture, and inflammation.

REGULATED NECROSIS

Regulated forms of cell death that produce necrotic morphology, including necroptosis and MPT-driven necrosis.

APOPTOSIS VS NECROSIS

Apoptosis is regulated/programmed cell death that usually affects individual cells and does not cause inflammation, while necrosis results from severe injury, affects groups or zones of cells, involves membrane rupture, and usually causes inflammation.

APOPTOSIS CELL SIZE

Cells shrink during apoptosis.

NECROSIS CELL SIZE

Cells swell during necrosis.

APOPTOSIS CELL MEMBRANE

The plasma membrane remains intact initially during apoptosis and apoptotic bodies remain membrane-bound.

NECROSIS CELL MEMBRANE

The plasma membrane eventually ruptures during necrosis.

APOPTOSIS CELLULAR CONTENTS

Cellular contents are packaged into membrane-bound apoptotic bodies.

NECROSIS CELLULAR CONTENTS

Cellular contents leak into the extracellular space after membrane rupture.

APOPTOSIS AND INFLAMMATION

Apoptosis usually does not cause inflammation.

NECROSIS AND INFLAMMATION

Necrosis usually causes inflammation because cellular contents are released into the extracellular space.

NUMBER OF CELLS AFFECTED IN APOPTOSIS

Apoptosis usually affects individual cells.

NUMBER OF CELLS AFFECTED IN NECROSIS

Necrosis often affects groups or zones of cells.

MAJOR MECHANISM OF APOPTOSIS

Caspase activation.

MAJOR MECHANISM OF NECROSIS

Loss of membrane integrity.

TYPICAL SETTINGS OF APOPTOSIS

Development, homeostasis, and DNA damage.

TYPICAL SETTINGS OF NECROSIS

Ischemia, toxins, infection, and trauma.

APPEARANCE OF APOPTOSIS

Apoptotic bodies.

APPEARANCE OF NECROSIS

Necrotic cells or tissue.

APOPTOSIS KEY FEATURES

Cell and organelle shrinkage, fragmentation into membrane-bound apoptotic bodies, and little to no inflammation.

PHYSIOLOGIC APOPTOSIS

Programmed cell death that is essential for normal biological processes.

FUNCTIONS OF PHYSIOLOGIC APOPTOSIS

Embryonic development, removal of unwanted cells, tissue remodeling, involution of organs, and removal of cells after withdrawal of hormones or growth factors.

PATHOLOGIC APOPTOSIS

Apoptosis caused by pathological conditions such as DNA damage, certain viral infections, toxic injury, and excessive or abnormal cellular stress.

APOPTOSIS AND DNA DAMAGE

Severe or abnormal DNA damage can trigger apoptosis.

APOPTOSIS AND VIRAL INFECTION

Certain viral infections can trigger pathologic apoptosis.

APOPTOSIS AND TOXIC INJURY

Toxic injury can trigger pathologic apoptosis.

APOPTOSIS AND CELLULAR STRESS

Excessive or abnormal cellular stress can trigger pathologic apoptosis.

MORPHOLOGIC APPEARANCE OF APOPTOSIS

Apoptosis is a controlled and tidy form of cell death characterized by nuclear condensation, nuclear fragmentation, cell shrinkage, membrane blebbing, and formation of apoptotic bodies.

PYKNOSIS

Chromatin condenses into dense, dark clumps, often near the nuclear membrane.

KARYORRHEXIS

Fragmentation of the nucleus into small pieces.

CELL SHRINKAGE IN APOPTOSIS

The apoptotic cell becomes smaller and more compact.

BLEBBING

Formation of bulges or blebs in the plasma membrane during apoptosis.

APOPTOTIC BODIES

Membrane-bound fragments containing pieces of nucleus, organelles, and condensed cytosol.

HETEROPHAGY

The process in which phagocytes recognize and engulf apoptotic bodies.

WHY APOPTOSIS DOES NOT CAUSE INFLAMMATION

The plasma membrane remains intact around apoptotic bodies, preventing cellular contents from spilling into the surrounding tissue.

APOPTOSIS AND NECROSIS CAN COEXIST

In damaged tissues, some cells may undergo apoptosis while other cells undergo necrosis.

MIXED APOPTOSIS AND NECROSIS

A pattern in which apoptosis and necrosis occur simultaneously in different cells within damaged tissue.

CASPASES

A family of proteases that regulate apoptosis and inflammation in multicellular organisms.

PROTEASES

Enzymes that break down proteins.

PROCaspase

An inactive precursor form of a caspase.

CASPASE CASCADE

A sequence in which caspases activate other caspases by cleavage, ultimately producing apoptosis or inflammatory responses.

CASPASES IN APOPTOSIS

Caspases are the primary executioners of apoptosis and carry out the regulated destruction of the cell.

CASPASES IN INFLAMMATION

Some caspases participate in inflammatory responses, including cytokine maturation and immune pathway activation.

CASPASES AND HOMEOSTASIS

By regulating cell death and inflammation, caspases contribute to overall homeostasis.

CASPASE ACTIVATION

Procaspases are initially inactive and become activated by cleavage from other caspases in response to death signals.

CASPASE SUBSTRATE CLEAVAGE

Activated caspases cleave specific protein substrates within the cell, initiating apoptosis or inflammatory processes.

MOLECULAR SCISSORS

Caspases can be thought of as the “molecular scissors” of apoptosis because they cut specific cellular proteins.

INITIATOR CASPASES

Caspases that start the apoptotic pathway.

EXECUTIONER CASPASES

Caspases that carry out the actual destruction of the cell.

CASPASE-8

An initiator caspase associated with the extrinsic apoptotic pathway.

CASPASE-9

An initiator caspase associated with the intrinsic apoptotic pathway.

CASPASE-2

An initiator caspase associated with DNA damage/p53 signaling.

CASPASE-10

An initiator caspase associated with the extrinsic pathway in some cells.

CASPASE-3

An executioner caspase that participates in the destruction of the apoptotic cell.

CASPASE-6

An executioner caspase that participates in the destruction of the apoptotic cell.

CASPASE-7

An executioner caspase that participates in the destruction of the apoptotic cell.

INITIATOR VS EXECUTIONER CASPASES

Initiator caspases start apoptotic signaling, while executioner caspases carry out the actual cellular destruction.

MAIN APOPTOTIC PATHWAYS

Extrinsic pathway and intrinsic pathway.

EXTRINSIC APOPTOTIC PATHWAY

A pathway triggered by external signals such as death ligands binding to death receptors.

INTRINSIC APOPTOTIC PATHWAY

A pathway triggered by internal cellular signals such as DNA damage or lack of growth factors and involving mitochondria.

EXTRINSIC INITIATOR CASPASE

Caspase-8, and sometimes caspase-10.

INTRINSIC INITIATOR CASPASE

Caspase-9.

DISC

Death-Inducing Signaling Complex formed during the extrinsic apoptotic pathway.

EXTRINSIC APOPTOSIS

The apoptotic pathway that begins outside the cell when extracellular death signals bind to death receptors on the plasma membrane.

DEATH RECEPTORS

Receptors on the plasma membrane that receive extracellular death signals and initiate extrinsic apoptosis.

FAS RECEPTOR

FasR; a death receptor involved in the extrinsic apoptotic pathway.

TNFR1

Tumor Necrosis Factor Receptor 1; a death receptor involved in extrinsic signaling.

TRAILR

TRAIL receptors; death receptors involved in the extrinsic apoptotic pathway.

FAS CD95/FAS LIGAND SYSTEM

A receptor-ligand system important for immune system homeostasis.

FASL

Fas ligand; an extracellular death ligand that binds Fas receptor.

FAS/FASL FUNCTION

The Fas/FasL system contributes to deletion of autoreactive T and B lymphocytes and destruction of virus-infected or transformed cells by cytotoxic T lymphocytes.

TNFR1/TNF-α SYSTEM

TNFR1 is activated by Tumor Necrosis Factor-alpha and can balance pro-inflammatory signaling with apoptotic signaling depending on intracellular conditions.

TNF-α

Tumor Necrosis Factor-alpha; ligand that activates TNFR1.

CTL

Cytotoxic T lymphocyte; cells involved in destruction of virus-infected or transformed cells through the Fas/FasL system described in the module.

EXTRINSIC APOPTOSIS SEQUENCE

Death ligand → death receptor → TRADD/FADD recruitment → DISC formation → procaspase-8 activation → caspase-8 → caspase-3/caspase-7 → apoptosis.

RECEPTOR TRIMERIZATION

Binding of an extracellular trimeric ligand such as FasL to its receptor causes three receptor molecules to aggregate on the cell membrane.

ADAPTER RECRUITMENT

Aggregated intracellular death domains recruit adapter proteins containing matching death domains.

FADD

Fas-Associated Death Domain; an adapter protein recruited during Fas signaling and involved in DISC formation.

TRADD

TNFR-Associated Death Domain; an adapter protein involved in death receptor signaling.

DEATH DOMAIN

An intracellular domain involved in recruiting adapter proteins during death receptor signaling.

DED

Death effector domain; the domain on FADD that recruits inactive procaspase-8 or procaspase-10.

DISC ASSEMBLY

FADD uses its death effector domain to recruit inactive procaspase-8 or procaspase-10, forming the Death-Inducing Signaling Complex.

PROCASPASE-8 IN DISC

The high local concentration of procaspase-8 within the DISC allows reciprocal autoproteolytic cleavage and production of active caspase-8.

INITIATOR CASPASE CLEAVAGE IN EXTRINSIC APOPTOSIS

Procaspase-8 is cleaved within the DISC to produce active caspase-8.

EXECUTIONER ACTIVATION BY CASPASE-8

Active caspase-8 directly cleaves and activates caspase-3, caspase-6, and caspase-7.

ENDONUCLEASES IN EXTRINSIC APOPTOSIS

Activated downstream pathways include endonucleases and proteases that dismantle the cell.

FLIP

FLICE-like inhibitory protein; an inhibitor of the extrinsic apoptotic pathway.

FLIP MECHANISM

FLIP binds to FADD within the DISC and, because it lacks enzymatic activity, prevents caspase-8 activation.

FLIP EFFECT

FLIP ↑ → caspase-8 activation ↓ → extrinsic apoptosis ↓.