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

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

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

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

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

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…)

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Secretion u continual - permanent - unregulated u pulsatory - regulated

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

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

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

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

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

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

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

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