1. General Pathology Pathology of Organels I. – Introduction The Secretory Process and Its Disorders Inst. Pathol.,1st Med. Faculty, Charles Univ. Prague Jaroslava Dušková

2. Pathology of Organels I - table of contents  The cell components & their function  Pathomorphology of the cell nucleus  quantitative  qualitative  Pathomorphology of the cytoplasm  cytosol  organelles  intracellular accumulations  water  proteins  lipids  glycogen  pigments,foreign bodies  Cellular secretion  types  organelles involved  sense

3. The Cell Components &Their Function 1. nucleus (incl. nucleolus and nuclear envelope) 2. cytoplasm v cytoplasmic matrix v cytoplasmic organelles 3. plasma membranes

4. The Cell Components &Their Function The nucleus (incl. nucleolus and nuclear envelope) chromosomes DNA, RNA, histones

5. The Cell Components &Their Function The nucleus functions – cell division – genetic information transcription & control

6. Cell Nucleus Pathology (1) Related to genom changes u quantitative: –binucleation, multinucleation – regular polyploidy (4n, 8n… 2 n n) - reactive change eg. in inflammation –adaptation u qualitative: –translocations, deletions, amplifications – aneuploidy – often in neoplasms (DNA densitometry, FISH, CGH…)

7. Neoplasia (Tumour) v DNA disease v Stepwise accumulation of genetic abnormalities v Escape of immunological clearing systems

8. p16 INK4a protein u inhibitor of cyclin dependent kinase u controled in healthy cells – undetectable u overexpressed as a result of HPV E7 protein u MARKER OF DYSPLASTIC CELLS

9. Cell Nucleus Pathology (2) Related to nucleolemma u quantitative: –invaginations - pseudoinclusions u qualitative: –thickening (irregular) –chromatin margination Nuclear inclusions (real) –viral, lipids, glycogen

10. The Cell Components &Their Function  ribosomes  endoplasmic reticulum  Golgi complex  lysosomes  peroxisomes  mitochondria  cytoskeleton  caveolae The cytoplasm (cytosol) cytoplasmic matrix cytoplasmic organelles

11. The Cell Components &Their Function The cytoplasm (cytosol) aqueous solution with enzymes

12. The Cell Components &Their Function The cytoplasm function – proteosynthesis (in coop. with organelles) – storage unit (fat, carbohydrates and secretory vesicles)

13. Intracellular Accumulations u water –hydropic degeneration u proteins – hyaline droplets u lipids – steatosis u glycogen – glycogenosis u pigments – melanin, ceroid, lipofuscin, hemosiderin u foreign bodies, crystals

14. Hydropic Degeneration u intoxications u sepsis u anoxia u starvation u functional overload u autolysis ENERGY DEFICIENCY

15. Intracellular Accumulations u water –hydropic degeneration u proteins – hyaline droplets u lipids – steatosis u glycogen – glycogenosis u pigments – melanin, ceroid, lipofuscin, hemosiderin u foreign bodies, crystals

16. Intracellular Accumulations u water –hydropic degeneration u proteins – hyaline droplets u lipids – steatosis u glycogen – glycogenosis u pigments – melanin, ceroid, lipofuscin, hemosiderin u foreign bodies, crystals

17. Intracellular Accumulations u water –hydropic degeneration u proteins – hyaline droplets u lipids – steatosis u glycogen – glycogenosis u pigments – melanin, ceroid, lipofuscin, hemosiderin u foreign bodies, crystals

18. Intracellular Accumulations u water –hydropic degeneration u proteins – hyaline droplets u lipids – steatosis u glycogen – glycogenosis u pigments – melanin, ceroid, lipofuscin, hemosiderin u foreign bodies, crystals

19. Intracellular Accumulations u water –hydropic degeneration u proteins – hyaline droplets u lipids – steatosis u glycogen – glycogenosis u pigments – melanin, ceroid, lipofuscin, hemosiderin u foreign bodies, crystals

20. The Cell Components &Their Function  ribosomes  endoplasmic reticulum  Golgi complex  lysosomes  peroxisomes  mitochondria  cytoskeleton  caveolae  vaults The cytoplasm - cytoplasmic organelles

21. The Cytoplasmic Organelles Functions (1) OrganelleCompositionFunction ribosomesRNA –protein complexes proteosynthesis endoplasmic reticulum cisternae,tubular channels proteosynthesis & transport Golgi complex (GC) smooth membranes & vesicles processing and packaging lysosomessacklike GC derived digestion

22. The Cytoplasmic Organelles Functions (2) OrganelleCompositionFunction peroxisomes lysosomes like producing or using H 2 O 2 detoxication mitochondria membrane bound energy production Oxydative fosforylation, cell signaling, pH control, Ca homeostasis

23. Mitochondrial DNA somatic mutations (point mutations and large deletions) and mtDNA variants in human thyroid pathology A study with emphasis on Hurthle cell tumors Máximo V et al, Am J Pathol 160:1857, 2002

24. Nuclear genes Ex. GRIM-19 Mt genes (Complex I, III, IV, V) Hürthle cell features Mitochondrial proliferation Activation of HIF-1 & Decreased apoptosis Tumourigenesis

25. Peroxisomes - microbodies up to 2 microns - catalase Function Degradation: substrate oxidation (etanol) Anabolism: synthesis of prostaglandin, cholesterol, billiary acids, plasmalogens, gluconeogenesis, transamination

26. The Cytoplasmic Organelles Functions (3) OrganelleCompositionFunction Cytoskeleton Microtubules & actin microfilaments Microvilli, cilia, flagella Caveolae Membrane indentations Shuttling material Vaults Octagonal barrrels like ribonucleoproteins Shuttling molecules

27. The Cell Components &Their Function The plasma membranes – cell surrounding – organelles enclosing – bilayer of lipids and proteins

28. Cell mechanism Membrane function Structure Compartmentalization, cytoskeleton & ER contacts, fluid & electrolyte balance ProtectionBarrier to toxins & foreign organisms/cells Activation of cell Hormones, mitogens, antigens, growth &proliferation factors StorageReceptors, transport, diffusion, exocytosis, endocytosis Cell to cell interaction Communication & attachment –junctional complexes, nutritive relationship, enzymes and antibody release

29. Secretion – exocrine (apical pole of the cell lumen, duct) – endocrine (basal pole of the cell blood) – paracrine influencing neighbouring cells – autocrine self influencing

30. Organelles Involved in Secretion u membrane type u maternal origin (ovum cytoplasm) u autoreplicative –granular (rough) endoplasmic reticulum –Golgi apparatus – lysosomes

31. Exocytosis and Its Disorders protein secretion on the granular endoplasmic reticulum cis Golgi network trans Golgi network (signal molecules attachment) Golgi Endoplasmic Reticulum Lysosomes

32. Secretion u continual - permanent - unregulated u pulsatory - regulated

33. Secretion u continual - permanent – unregulated vesicle transport – protocolagen, proteoglycans, viral particles Targetting: immunoglobulins without and after stimulation

34. Secretion u pulsatory - regulated – exocrine mucin or zymogen granules secretion – endocrine cells – neurons – T-lymphocytes – heparinocytes –thrombocytes – granulocytes – endothelia membrane budding coating proteins

35. Secretion Disorders defects of synthesis v product itself v auxilliary proteins retention in GER (inborn endoplasmic reticulum storage diseases) hyaline droplets (Russel bodies)

36. Neuroendocrine Secretion Disorders defects of synthesis v product itself v auxilliary proteins regulation disorders on the receptor level

37. Neuroendocrine Secretion u dense core granules u secretory vesicles (small synaptic vesicles)

38. Membrane Components of Secretory Granules and Vesicles –Synaptophysin (synaptic vesicle protein) –Neuron Specific Enolase –S-100 protein identification of neuroendocrine neoplasms

39. Juxtacrine Secretion (?) / Signaling u contact (- dependent) signalling u cell adhesion (inflammatory cells… neoplastic cells… u transmitted via oligosaccharide, lipid, or protein components of a cell membrane u Unlike other types of cell signaling (such as paracrine and endocrine), juxtacrine signaling requires physical contact between the two cells involved. u Juxtacrine signaling has been observed for some growth factors, cytokine and chemokine cellular signals. pathology of INFLAMMATION, TUMOURS

40. Lipofuscin and its meaning in Neurons ? u small amounts – probably no influence on function – reflects slow decrease in lysosomal enzymes activities u increased in certain neurodegenerations (m. Alzheimer, motor neuron disease…) u CEROID-LIPOFUSCINOSIS probably a group of heterogenous diseases with variable severity and inborn enzyme defects (autosomal recessive inheritance most frequent) THRESHOLD