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Sub-cellular Pathology

Sub-cellular Pathology. CELL ORGANELLES AND DISEASE Fiona McKie-Bell BOD. Subcellular Pathology. ‘ Identification of the primary lesion in any pathological process in terms of the organelles and metabolic processes that are involved’. Contents. Endocytosis and lysosomes

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Sub-cellular Pathology

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  1. Sub-cellular Pathology CELL ORGANELLES AND DISEASE Fiona McKie-Bell BOD

  2. Subcellular Pathology • ‘Identification of the primary lesion in any pathological process in terms of the organelles and metabolic processes that are involved’

  3. Contents • Endocytosis and lysosomes • Organelle disorders • Named diseases • Exam questions

  4. Disorders • PM • Permeability • Enzymes • Cytolysins • C’ • Inherited Disorders • Nucleus • Chromosomal abnormalities • Single gene defects • Toxic damage • Nutritional deficiencies • Mitochondrion • Endoplasmic reticulum • Cytoskeleton • Lysosomes • General sig. In pathology • Resistance • Inappropriate cellular release (intra and extra) • Storage diseases

  5. Differential Centrifugation • Involve stepwise increases in the speed of centrifugation. • At each step, more dense particles are separated from less dense particles • Successive speed of centrifugation is increased until the target particle is pelleted out.

  6. The Plasma Membrane • 'Fluid mosaic model’ • Chemically distinct from most other membranes in the cell • contains more sphingomyelin and cholesterol. • Many extrinsic proteins have carbohydrate moieties attached to them • important in determining antigenicity of cells e.g. blood group antigens

  7. Structure of a typical cell membraneFigure 10.10:(Mathews, Van HoldeBiochem 3rded)

  8. Effects on Permeability of the Plasma Membrane • Affect the sodium/potassium ATPase (sodium pump) • Maintains electrolyte balance • Ouabain(a plant glycoside) Digitalis(a plant steroid), Tetrodotoxin, (puffer fish) Saxitoxin(microscopic algae - 'the red tide') • Can be used in the treatment of cardiac conditions • Increase the force of contraction of heart muscle by altering the excitability of the tissue (a function of the sodium and potassium concentrations across the membrane). • http://highered.mcgraw-hill.com/sites/0072495855/student_view0/chapter2/animation__how_the_sodium_potassium_pump_works.html

  9. Effects on Permeability of the Plasma Membrane • Binds to the sodium channel in the plasma membrane and blocks ion movement. • Tetrodotoxin- neurotoxin found in some organs of the puffer fish • Saxitoxin is produced by microscopic algae ('the red tide') • One of only two naturally occurring toxins to be classified as a Schedule 1 Chemical Warfare agent ...and the waters that were in the river were turned to blood. And the fish that were in the river died; and the river stank and the Egyptians could not drink of the water of the river... Exodus 7: 20-21

  10. Chemical & biological warfare • 1950s – US experiments with saxitoxin as chemical weapon • 1000x more toxic than the nerve gas, sarin • Used as suicide pill for U-2 spyplane pilots • 1970 – Richard Nixon ordered destruction of all stocks • Now used in research into sodium ion channels and nervous disorders

  11. Effects of Enzymes on the Plasma Membrane - Antigenicity • Affecting antigenicity of cells by removing components from the extracellular surface of the plasma membrane e.g. • Neuraminidase(removes carbohydrate sialic acid groups) • Influenza (H1N1) Haemaggluttinin, Neuramaminidase -plays its major role after virus leaves an infected cell - ensures virus doesn't get stuck on the cell surface by clipping off the ends of these polysaccharide chains. • Trypsin (removes glycopeptides).

  12. Effects of enzymes on the plasma membrane - Lysis • Phospholipases • Hydrolysephospholipid components of the plasma membrane • Lead to the formation of lysophosphatides (very potent surfactant molecules) • Cell lysis occurs • Found in snake venoms, some cytolytic pathogenic bacteria (e.g.Clostridiumperfringens.) • Cytolysin e.g. Streptolysin O • toxin produced by Streptococci • A cholesterol-dependent cytolysin (CDC) • causes cell lysis by interacting with the cholesterol of the host plasma membrane, disrupting the membrane and forming a large pore

  13. Membrane Phospholipids Sphingosine – alcohol amine

  14. Action of Phospholipases Found in Snake Venoms

  15. Complement-related membrane injury • When complement becomes bound to a cell surface, its activation leads to the formation of a 'membrane attack complex' • Causes lysis of the cell • e.g. red cells in incompatible blood transfusions

  16. Inherited membrane disorders • Familial Hypocholesterolaemia (see later) • Hartnup Disease • defect in the transport proteins for uptake of the essential amino acid tryptophan by intestinal epithelial cells. • Trp is an important precursor of the vitamin nicotinic acid • clinical signs of Hartnup disease are similar to those of the vitamin deficiency disease, pellegra (3Ds) • (Dementia, Dermatitis, and Diarrhoea)

  17. Cystic Fibrosis • Due to an inherited defect in the cystic fibrosis trans-membrane conductance regulator (CFTR) • CFTR is involved in chloride ion transport across the plasma membrane • Important in creating sweat, mucus and digestive juices. • Multiple theories on Cl transport changes and symptoms

  18. Damage to the plasma membrane - diagnostic aspects • Changes in the permeability of the plasma membrane can be detected by • histochemical methods • biochemical methods • very useful in the diagnosis of certain diseases

  19. The Nucleus • Contains the genetic material of the cell • DNA can be affected in a number of ways. • Chromosomal abnormalities • Single gene defects • Toxic damage • Nutritional deficiencies

  20. Chromosomal abnormalities • Alteration in the diploid number • e.g. Down syndrome (trisomy 21) - congenital abnormalities • Chromosomal breakages • e.g. ataxia-telangiectasiasyndrome • ATM Gene regulates cell cycle checkpoints, repair dsDNA, regulating p53, BRCA1 and CHEK2, telomere repair • Symptoms • Dysfunction of the cerebellum • ataxia (unsteadiness or incoordination of limbs, posture, and gait) • telangiectasia of the eyes and skin (a complex of abnormally and permanently dilated blood vessels) • severe immunological deficiency • ‘radiosensitivity’ leading to leukaemia

  21. Down’s Syndrome Trisomy 21

  22. Single Gene Defects • No obvious morphological abnormality in the nucleus or chromosomes • Mutation (even single aa change) • e.g. PKU, SCD (val-glu sub.)

  23. Toxic Damage • Chemical carcinogens • e.g. alkylating agents such as the nitrogen mustards • Cancer chemotherapy • e.g. 5-fluorouracil, methotrexate - interfere with synthesis of DNA precursor • vincristine - damages the mitotic spindle (not DNA)

  24. Nutritional Damage • Folic acid or Vitamin B12 • deficiencies of these vitamins affect DNA synthesis • result in large nuclei, but with less DNA content than optimal for mitosis • mainly evident in red cell precursor cells in bone marrow

  25. The Mitochondrion • Prime target in cellular damage caused by hypoxia • Affected by ‘uncouplers' of electron transport such as dinitrophenol • The enzymes of the electron transport chain are inhibited by poisons such as rotenone and cyanide

  26. Mitochondrial diseases • Can affect any organ at any age • Severely debilitating and often fatal • In USA, 50 million adults suffer from diseases involving mitochondrial dysfunction • Cancer, infertility, diabetes, heart disease, blindness, deafness, kidney disease, liver disease, stroke, migraine • Ageing, Parkinson’s disease, Alzheimer’s disease • Of 4 million children born in US per year, 4,000 develop mitochondrial disease • Many diseases still being discovered • No cure

  27. Mitochondrial DNA • The mitochondrion is the only organelle apart from the nucleus that contains DNA • Circular DNA (linear in nucleus) • Mitochondrial DNA maternal inheritance • important implications in genetic analysis involving family histories

  28. Disorders of mitDNA • Some inherited diseases are due to defects in genes in mitochondrial DNA • e.g. Leber's Hereditary Optic Neuropathy (LHON). • Rare disease - results in blindness (by 15-35 years) • Due to defect in the NADH dehydrogenase (in the electron transport chain). • Reduced ATP formation.

  29. LHON • Rare disorder - maternal transmission • Males never transmit LHON to offspring • Females less frequently affected than males • Results in degeneration of the optic nerve • (nerves very dependent on ox phos) • Main mutation in the NADH dehydrogenase gene is at bp11778 • his - arg mutation in the enzyme

  30. The Endoplasmic Reticulum • Smooth endoplasmic reticulum is the site of cytochrome P450 mixed function oxidase (CYP) • enzyme essential in the detoxification of many substances. • Exposure of liver cells to certain drugs can result in proliferation of the SER • This can have serious consequences for individuals who are taking more than one drug.

  31. Induction of CYP • CYP in the SER can be induced by several substances • ethanol, acetone, polycyclic hydrocarbons, and phenobarbital • May give rise to an increased rate of hydroxylation and subsequent excretion of therapeutic drugs • Induction of CYP by one drug may stimulate the metabolism of other drugs that are also substrates for the enzyme

  32. Example 1 • Rifampicin (anti-tuberculosis agent) • induces CYP • Increases clearance of oral contraceptives • Increased incidence of pregnancy in women given both drugs.

  33. Example 2 • Phenobarbital (a barbiturate) induces CYP • Warfarin (anticoagulant) require caution with other meds. • V sensitive to being metabolised rapidly by induced CYP • If CYP- Inducing drugs are withdrawn, CYP levels fall • If the warfarin dose is not also reduced • Haemorrhage • In some cases DEATH!

  34. The Cytoskeleton • Microtubules (20 – 25 nm diameter) • Actin filaments (6 – 8 nm) • Myosin filaments (15 nm) • Intermediate filaments (10 nm)

  35. Cytoskeletal Lesions • Defects in proteins of the cytosleleton affect - • Cell locomotion • e.g. leukocyte migration • Phagocytosis • sperm motility (leading to infertility) • Movement of intracellular organelles • e.g. Chediak-Higashi syndrome, in which there is impaired fusion of lysosomes with phagosomes containing bacteria.

  36. Accumulations/Disorders of cytoskeletal proteins • Alzheimer’s disease • neurofibrillary tangle - composed of neurofilaments and microtubular proteins • Mallory body is characteristic of Alcoholic Liver Disease. • composed of intermediary filaments (mainly prekeratin) • DMD • Gene (1987) ‘Dystrophin’ • Structurally related to spectrin • Plays key role in anchoring cytoskeleton to extracellular matrix • Such anchorage may enable the plasma membrane to withstand the stress of muscle contraction

  37. LYSOSOMES • Structure and formation • Enzymes • Mechanisms • Heterophagy • Exocytosis • Autolysis • Crinophagy • Sig. in pathology • Toxin • Micro-organisms • Inappropriate release and disease states • Storage disorders See also lysosome slides

  38. Lysosomes • Vesicle surrounded by single membrane • Distinct from mitochondria and microbodies • Isolated by differential centrifugation • Over 60 hydrolytic enzymes (acid pH optima) known to be lysosomal in origin. Include – • Peptide hydrolases • Glycosidases • Nucleases • Phospholipases • Phosphatases • Sulphatases

  39. Lysosomal enzymes • Most are glycoproteins with acid pH optim • Some (e.g. cathepsin G, and elastase) are active at neutral pH • The bacteriocidal enzymes lysosyme and myeloperoxidase are found in polymorphonuclear leucocytes • Lysosomes - capable of degrading almost any material of biological origin

  40. Lysosomal membrane • Contains cholesterol and sphingomyelin • Also present in the plasma membrane • but not to any extent in other membranes in the cell • Reflects exchange of material between the lysosomal amd plasma membranes during endocytosis and exocytosis

  41. Origin of lysosomes • Synthesis of lysosomal protein takes place in the rough endoplasmic reticulum • The enzymes are packages into vesicles by the Golgi apparatus and become PRIMARY LYSOSOMES • Primary lysosomes fuse with vesicles of various origin to become SECONDARY LYSOSOMES

  42. Secondary lysosomes • Fusion of a primary lysosome with a vesicle containing material to be digested means that the hydrolytic enzymes are not released into the cytoplasm (where they could cause damage) • Secondary lysosomes have a heterogeneous appearance because of the variety of material contained in endocytotic vesicles or phagosomes

  43. Mechanisms involving lysosomes • Heterophagy • Breakdown of extracellular material taken up by endocytosis or phagocytosis • Exocytosis • Release of the contents of an intracellular vesicle without loss of cytoplasm (reversal of endocytosis) • Autophagy • Digestion of intracellular material (cytoplasm and organelles) within a secondary lysosome • Crinophagy • Disposal of excess secretory proteins

  44. Importance of Lysosomes in Pathology • Lysosomes have particular importance in pathology because they are: • involved in reactions to toxic substances • involved in digestion of foreign microorganisms • contain many hydrolytic enzymes,which, if released inappropriately may cause both intracellular and extracellular damage

  45. 1. Autolysis of Tissues • a) Programmed Cell Death (Apoptosis) • interdigital cell death in foetus - resulting in 5 fingers • involution of the uterus and ovaries post menopause • atrophy of breast tissue following weaning

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