Subcellular Responses

Transcript

1. Subcellular Responses to Injury Lysosomal turnover, ER adaptation, mitochondria, cytoskeleton and proteostasis
2. Subcellular adaptation precedes visible disease Organelles respond specifically to demand or stress. Lysosomes adjust the disposal of extracellular and intracellular material. Smooth ER may expand during xenobiotic metabolism. Mitochondria change number, size, shape and function. Cytoskeletal defects perturb structure, trafficking and motility.
3. The organelle-level framework Smooth endoplasmic reticulum P450-linked xenobiotic processing. Mitochondria Cytoskeleton Chaperones Ubiquitin-proteasome Structural integrity, movement and intracellular transport. Protein folding and stress resistance. Selective clearance of damaged proteins. Lysosomes Heterophagy and autophagy. Energetic adaptation and cell-death signaling.
4. Lysosomes are degradative compartments Acidic hydrolases act on material delivered to lysosomes. Hydrolases function optimally in an acidic vesicular environment. The system removes damaged organelles, internalized microbes and cellular debris. Primary lysosomes fuse with incoming cargocontaining vesicles. Failure of degradation can lead to intracellular substrate accumulation.
5. Heterophagy and autophagy Process Cargo origin Example Heterophagy Outside cell Neutrophil ingests bacteria Autophagy Inside same cell Damaged mitochondrion recycled Both routes deliver material for lysosomal degradation.
6. Heterophagy: extracellular cargo 01 02 03 04 05 Endocytosis / phagocytosis Endosome / phagosome Lysosomal fusion Degradation Residual body Cargo internalized Membranebound cargo Hydrolases delivered Metabolites released Indigestible remnants persist Phagocytosis is especially important in professional phagocytes.
7. Autophagy: intracellular quality control The cell reclaims cytoplasm under stress. Cytoplasmic cargo is enclosed by a doublemembrane autophagosome. Fusion with lysosomes produces an autolysosome. Catabolites can support metabolism during transient starvation. Autophagy also selectively removes dysfunctional mitochondria (mitophagy).
8. Autophagic flux 01 02 03 04 05 Cargo recognition Isolation membrane Autophagoso me Lysosomal fusion Recycling Unneeded or damaged constituents Engulfs material Double membrane formed Hydrolytic destruction Amino acids and lipids reutilized A larger autophagosome count may mean induction OR blocked clearance.
9. Autophagy in injury and disease Usually adaptive; context can change the outcome. Starvation activates recycling and conserves cell resources. Defective autophagic flux can aggravate protein and organelle accumulation. Autophagy is implicated in neurodegeneration and some storage disorders. The mere presence of autophagic vacuoles does not prove “autophagic cell death.”
10. Residual bodies and lipofuscin Incomplete lysosomal digestion can leave persistent granules. Residual bodies contain material resistant to enzymatic degradation. Lipofuscin pigment is a common age-related residual product. It is visible in long-lived cells, including neurons and cardiomyocytes. Lipofuscin is generally a marker of wear rather than a primary lethal lesion.
11. Smooth ER induction Enzyme expression and membrane expansion accompany repeated xenobiotic exposure. Hepatocyte smooth ER contains important cytochrome P450 enzymes. Some drugs induce P450 transcription and increase ER volume. Enhanced metabolism may reduce exposure to the inducing drug or alter other medications. Metabolic intermediates can themselves be toxic under some conditions.
12. Drug-induced smooth ER adaptation 01 02 03 04 05 Repeated xenobiotic Transcription al response Smooth ER proliferation Faster biotransform ation Clinical interaction Enzyme inducer exposure P450 isoforms increased More metabolic membrane Altered clearance Efficacy / toxicity may change This is enzyme induction, not a universal effect of every medication.
13. Mitochondria remodel with demand Number, size and ultrastructure are dynamic. Biogenesis can increase mitochondrial content in energetically active cells. Fission and fusion help maintain quality and distribute mitochondria. Swelling can accompany reversible injury or become severe in lethal injury. Some conditions produce abnormally enlarged mitochondria (“megamitochondria”).
14. Mitochondrial changes in injury Energetic failure can initiate a death cascade. Loss of membrane potential reduces oxidative ATP generation. Reactive oxygen species can amplify injury. Calcium overload alters permeability and cellular signaling. Outer membrane permeabilization can release cytochrome c and activate apoptosis.
15. Mitophagy is mitochondrial quality control Damaged organelles are selectively routed to lysosomes. Loss of mitochondrial membrane potential can stabilize PINK1 on the outer membrane. Parkin-dependent ubiquitination recruits autophagic machinery in relevant contexts. Mitophagy reduces persistence of highly dysfunctional mitochondria. Quality-control failure can worsen energy deficiency and oxidative stress.
16. Mitochondrial disorders: pathology correlations Morphology must be combined with clinical genetics. Mitochondrial myopathies may show abnormal mitochondrial proliferation or cristae. Ragged-red fibers can appear with modified Gomori trichrome staining. Oncocytic neoplasms characteristically have abundant mitochondria. Mitochondrial appearance alone rarely specifies a particular genotype.
17. Four major cytoskeletal systems Actin microfilaments Microtubules Shape, contraction and phagocytic movement. Cilia, mitotic spindle and intracellular cargo transport. Intermediate filaments Myosin motors Mechanical resilience; cell-type-specific proteins. Actin-based contractility and organelle movement.
18. Microtubules and motile cilia Dynein-driven axonemal function is necessary for mucociliary clearance. Axonemal microtubules provide structural tracks for ciliary beating. Dynein defects can reduce ciliary motility and impair sperm flagella. Primary ciliary dyskinesia can cause recurrent airway infections and infertility. Some patients with dynein-associated defects have situs inversus.
19. Actin cytoskeleton: injury consequences Dynamic actin networks support cortical integrity. Disruption impairs cell shape, adhesion, migration and phagocytosis. Membrane blebbing reflects disturbed membrane–cortex interactions. Myosin and actin cooperate in contraction and cellular movement. Actin-dependent changes are prominent in injured epithelial cells.
20. Intermediate filaments: tissue signatures Expression patterns are diagnostically useful. Keratins occur in epithelial cells and many carcinomas. Vimentin labels many mesenchymal cells; desmin characterizes muscle differentiation. Neurofilaments are abundant in neurons; GFAP is a glial intermediate filament. Protein aggregates may reflect abnormal assembly or degradation.
21. Diseases of intermediate-filament proteins Mallory–Denk bodies Neurofibrillary tangles Keratin-containing aggregates in hepatocytes. Abnormal tau, a microtubule-associated protein, not a neurofilament inclusion. Desmin-related myopathies Epidermolysis bullosa simplex Abnormal intermediate filament organization. Mutations in basal keratins impair epidermal mechanical resilience.
22. Heat-shock proteins and chaperones Protein quality control is part of the cell-stress response. Molecular chaperones facilitate correct folding and assembly of proteins. Stress increases production of selected heatshock proteins. Chaperones limit aggregation and can refold damaged proteins. Persistently misfolded proteins are targeted for degradation or stress signaling.
23. Unfolded protein response: three arms The ER initially prioritizes restoration of protein homeostasis. IRE1, PERK and ATF6 are major ER stress sensors. They alter translation, folding capacity and degradation pathways. Acute responses can be protective and reversible. Persistent stress may activate CHOP-linked and other prodeath signaling.
24. Protein quality-control decision 01 02 03 04 05 Nascent / damaged protein Molecular chaperones Persistent misfolding Proteasome or autophagy Unresolved stress Folding needed Attempt refolding Ubiquitination and targeting Protein / aggregate degradation ER response, dysfunction, apoptosis Proteasomes process many soluble proteins; autophagy can clear large aggregates and organelles.
25. The ubiquitin-proteasome pathway Selective degradation regulates intracellular protein abundance. E1, E2 and E3 activities build ubiquitin signals on protein substrates. The 26S proteasome degrades many ubiquitinated proteins. It removes damaged proteins and controls signaling and cell-cycle regulators. Overwhelmed proteostasis can contribute to degenerative pathology.
26. Misfolded proteins in neurologic disease Deposition and toxicity are linked but not identical. Tau misfolding and aggregation are important in several neurodegenerative disorders. Prion diseases involve abnormal conformational propagation of prion protein. Certain amyloidoses contain extracellular fibrillar protein deposits. Mechanisms involve proteostasis disturbance, trafficking and secondary injury.
27. Applied reasoning: drug tolerance A medication repeatedly induces hepatic cytochrome P450 enzymes and expands smooth ER. Why might the same dose have a smaller effect over time?
28. Applied reasoning: ciliary dysfunction A patient has chronic sinusitis, recurrent bronchial infections, infertility and laterality abnormalities. Which subcellular apparatus is most likely dysfunctional?
29. Organelle responses: integrated summary Lysosomal systems SER Mitochondria Recycling and degradative clearance. Metabolic adaptation and xenobiotic biotransformation. ATP, ROS and deathsignaling regulation. Cytoskeleton Proteostasis Shape, mechanical stability and motility. Chaperone rescue, proteasomal and lysosomal degradation.
30. Suggested reading Robbins, Cotran & Kumar Pathologic Basis of Disease · Chapter: Cell Injury, Cell Death, and Adaptations For further study: correlate the molecular mechanisms with gross and microscopic pathology. Illustrative pathways are original schematics; selected histology images are retained from the supplied teaching material.