[01.02] Cell Injury & Death (Mechanisms of Cell Injury, Apoptosis, Intracellular Accumulations, Pathologic Calcifications) V2.2

Programmed cell death

What is apoptosis described as, indicating its controlled nature?

Tight regulation and organization

How does apoptosis differ from necrosis in terms of control?

Intrinsic enzymes that degrade own DNA and proteins

What is activated within cells to carry out apoptosis?

Apoptotic bodies and cytoplasmic blebs

What are the characteristic fragments formed during apoptosis that are later phagocytosed?

Phagocytes, usually macrophages

What typically ingests and degrades apoptotic bodies?

No inflammation

What is a key difference between apoptosis and necrosis regarding the immune response?

Physiologic and pathologic states

In what two general conditions may apoptosis occur?

Embryogenesis

What developmental process involves cells of primordial structures undergoing apoptosis during involution?

Involution of tissues after hormone withdrawal

What broad category of physiologic apoptosis includes endometrial breakdown during the menstrual cycle and ovarian follicular atresia?

Ovarian follicular atresia

Give an example of physiologic apoptosis related to menopause.

Regression of lactating breast after weaning

What happens to breast tissue via apoptosis when it's no longer needed for lactation?

Prostatic atrophy

What specific tissue undergoes atrophy due to lost testosterone via apoptosis?

Immature B-cells in marrow and thymus and lymphocytes that do not express useful antigen receptors

Give examples of proliferating cell populations that regularly undergo apoptosis.

Autoimmune diseases and lymphoma

What can overproliferation of lymphocytes that do not express useful antigen receptors cause?

Elimination of self-reactive lymphocytes

What intrinsic mechanism prevents autoimmune disease?

Neutrophils in an acute inflammatory response and lymphocytes at the end of the immune response

Give examples of host cells that die via apoptosis after serving their purpose in an immune response.

DNA damage, accumulation of misfolded proteins, infections, pathologic atrophy after duct obstruction

List the four main categories of pathologic apoptosis.

Ionizing radiation, cancer chemotherapy, hypoxia

List three common causes of DNA damage that can lead to apoptosis.

When DNA repair mechanisms get overwhelmed

When does apoptosis occur in response to DNA damage?

p53 protein (from TP53 gene)

What protein keeps cells in G1 phase or initiates apoptosis if DNA damage is too severe?

Cancer formation

What does p53 initiate apoptosis to prevent if DNA damage is too much?

Mutations of p53 protein

What can lead to several kinds of cancers regarding the p53 protein?

Unfolded protein response

What is the cell's compensatory mechanism when misfolded proteins accumulate?

Decreasing translation, increasing chaperone proteins, enhancing proteasomal degradation

What three actions does the cell take during an unfolded protein response to cope with misfolded proteins?

ER stress

What occurs if cells are unable to cope with accumulated misfolded proteins?

Caspases

What enzymes are activated by ER stress to execute apoptosis?

Degenerative diseases of the CNS like Alzheimer’s disease

What type of diseases are implicated with the accumulation of misfolded proteins?

Induced by the virus itself (e.g., HIV, adenovirus) or caused by host immune response (e.g., Hepatitis)

How can apoptosis occur during infections?

Cytotoxic T-cell response (CD8+ lymphocyte)

What immune response is induced by infection that kills infected cells?

Ductal stones or obstructions

What can lead to atrophy of ductal epithelial cells in organs like the pancreas, parotid, or kidney?

Cell shrinkage

What morphologic alteration in apoptosis results in a small cell with dense cytoplasm and a visible color change?

Chromatin condensation

What is the most characteristic morphologic alteration in apoptosis, appearing as aggregation of chromatin peripherally under the nuclear membrane?

Small, round, eosinophilic structure with dense nuclear chromatin

How does an apoptotic cell appear on Hematoxylin and Eosin (H&E) stain?

Activation of caspases

What is the primary mechanism of apoptosis?

Cysteine proteases that cleave proteins are aspartic residues

Describe caspases chemically.

Proenzymes/zymogens

What form do caspases start as before being cleaved to become activated?

Initiation phase

What phase of apoptosis occurs when caspases become catalytically active and cascade of other caspases are released?

Execution phase

What phase of apoptosis involves caspases triggering degradation of critical cellular components?

Intrinsic (mitochondrial) pathway and Extrinsic (death receptor) pathway

What are the two distinct pathways of apoptosis?

Increased permeability of the mitochondrial outer membrane

What characterizes the initiation of the intrinsic pathway?

Cytochrome c

Name a key death-inducing pro-apoptotic molecule released into the cytoplasm from mitochondria.

BCL2 (B cell lymphoma) family of proteins

What family of proteins regulates the intrinsic pathway?

Pro-apoptotic and Anti-apoptotic

What are the two main functional groups of BCL2 family proteins?

BCL2, BCL-XL, MCL1

List three anti-apoptotic BCL2 family proteins.

Prevent leakage of pro-apoptotic proteins into the cytoplasm

What is the function of anti-apoptotic BCL2 family proteins?

BAX and BAK

List two pro-apoptotic BCL2 family proteins.

Oligomerize and increase permeability of mitochondrial membrane

What is the function of pro-apoptotic BAX and BAK proteins?

BAD, BIM, BID, Puma, Noxa

List five examples of Regulated Apoptosis Initiators (BH3-only Proteins).

Sensors of cellular stress and damage

What is the role of BH3-only proteins?

Tip the balance towards apoptosis or cell survival

How do BH3-only proteins regulate the intrinsic pathway?

Deprivation of survival signals, DNA damage, accumulation of misfolded proteins

List three stimuli that can trigger apoptosis via the intrinsic pathway.

Upregulation of BH3-only proteins

What is the first step when a stimulus for apoptosis is detected in the intrinsic pathway?

Activate BAX and BAK and inhibit BCL2 and BCL-XL

What do BH3-only proteins do to tip the balance towards apoptosis?

APAF-1 (Apoptosis-activating factor-1)

What protein does Cytochrome c bind to in the intrinsic pathway?

Apoptosome

What hexamer is formed when Cytochrome c binds to APAF-1?

Caspase-9

What critical initiator caspase of the mitochondrial pathway does the apoptosome bind to?

Smac/DIABLO

What additional proteins enter the cytoplasm to prevent apoptosis from stopping in the intrinsic pathway?

Physiologic inhibitors of apoptosis (IAPs)

What do Smac/DIABLO neutralize?

Engagement of plasma membrane death receptors on a variety of cells

What characterizes the initiation of the extrinsic pathway?

TNF (tumor necrosis factor) family

What family do death receptors belong to?

Cytoplasmic domain (aka death domain)

What part of death receptors delivers apoptotic signals via signal transduction?

TNFR1 and Fas (CD95)

List two best-known types of death receptors.

Fas ligand (FasL)

What binds to Fas (CD95) to initiate the extrinsic pathway?

Cytotoxic T cells

Where is FasL typically found?

Fas-associated death domain (FADD)

What complex is formed when three or more Fas proteins come together and their death domains associate?

Caspase 8 (or Caspase 10 in humans)

What initiator caspase does FADD bind to?

FLIP protein

What protein inhibits the extrinsic pathway?

Binds pro-caspase-8, preventing it from being cleaved

How does FLIP protein inhibit the extrinsic pathway?

Viruses

What uses FLIP protein to protect infected cells from being destroyed?

Caspases 3 and 6

List two key executioner caspases.

Activate DNases by cleaving their inhibitors and degrade structural components of nuclear matrix

What do executioner caspases do?

Phosphatidylserine flipping out to the outer side of the membrane

What membrane change promotes phagocytosis of apoptotic bodies?

Thrombospondin

Name a protein expressed by apoptotic fragments that recruits phagocytes.

Antibodies and complement (C1q)

What can coat apoptotic bodies to further attract white blood cells?

Prevent inflammation and necrosis

What do the processes of apoptotic body removal prevent?

Leakage of proteins (cytochrome c) from the mitochondria into the cytoplasm

Summarize the key event in the mitochondrial (intrinsic) pathway.

FasL and Fas binding

Summarize the key event that initiates the death receptor (extrinsic) pathway.

Necroptosis

What hybrid cell death pathway combines features of apoptosis and necrosis?

Morphologically and biochemically resembles necrosis (inflammation, leukocyte recruitment)

How is necroptosis similar to necrosis?

Signal transduction

How is necroptosis similar to apoptosis?

No activation of caspases

What distinguishes necroptosis from apoptosis regarding caspase activation?

Ligation of TNFR1

What initiates necroptosis, similar to the extrinsic pathway of apoptosis?

RIPK1 and RIPK3 (receptor-interacting protein kinases)

What proteins are recruited following TNFR1 ligation in necroptosis?

MLKL protein

What protein is phosphorylated by RIPK3, leading to plasma membrane degradation in necroptosis?

Formation of mammalian growth plate

Give a physiologic example of necroptosis.

Steatohepatitis, acute pancreatitis, ischemia-reperfusion injury, neurodegenerative diseases (e.g., Parkinson’s disease)

List four pathologic conditions where necroptosis may occur.

Backup host defense

What role does necroptosis play when viruses have caspase inhibitors?

Pyroptosis

What cell death pathway is characterized by fever and the release of inflammatory mediators?

IL-1 (fever-inducing cytokine)

What cytokine is associated with pyroptosis?

Microbial products recognized by immune receptors

What initiates pyroptosis?

Inflammasomes

What multiprotein complex is activated by microbial products in pyroptosis?

Caspase-1 (IL-1 beta converting enzyme)

What caspase is activated by inflammasomes in pyroptosis?

Caspases 1, 4, and 5

What caspases induce cell death in pyroptosis?

Ferroptosis

What cell death pathway is caused by excessive intracellular iron or reactive oxygen species (ROS)?

Glutathione-dependent antioxidant defenses

What is overwhelmed in ferroptosis?

Unchecked membrane lipid peroxidation

What results from the overwhelming of antioxidant defenses in ferroptosis?

Loss of mitochondrial cristae and rupture of the outer mitochondrial membrane

What are the key morphologic changes seen in ferroptosis?

Cancer, neurodegenerative disease, stroke

List three conditions where ferroptosis is implicated.

Nature, duration, and severity of injury

What determines the response to cell injury?

Type, state, and adaptability of the cell

What determines the consequences of cell injury?