Chapter 2 part 4 Flashcards
3 types of autophagy
1) chaperone-mediated = direct translocation across the lysosomal membrane by chaperone proteins
2) microautophagy = inward invagination of lysosomal membrane for delivery
3) macroautophagy = major form of autophagy involving sequestration and transportation of portions of cytosol in a double-membrane bound authophagic vacuole
Steps of autophagy
1) initiation- triggered by formation of invitation complex and nucleation complex
2) elongation- via LC3
3) maturation of autophagosome
4) fusion with lysosome
5) degradation
4 main pathways of abnormal intracellular accumulations
1) abnormal metabolism (fatty liver)
2) defect in protein folding/transport ;eating to accumulation of abnormal proteins
3) lack of enzyme leading to accumulation of endogenous material (lysosomal storage disease)
4) ingestion of indigestable materials leading to accumulation of exogenous materials
Steatosis
accumulations of triglycerides within parenchymal cells ; often seen in liver, heart, muscle, kidney
Causes: toxin, protein malnutrition, diabetes, obesity, anoxia
Atherosclerosis
smooth muscle cells and macrophages within the intimal layers of aorta and large arteries are filled with lipid vacuoles made up of cholesterol (foam cells)
Xanthomas
intracellular accumulation of cholesterol within macrophages; clusters of foamy cells found in sub epithelial connective tissue of skin and in tendons
Cholesterolosis
focal accumulations of cholesterol-laden macrophages in the lamina propria of the gallbladder
Niemann-Pick disease, type C
lysosomal storage disease caused by mutation affecting an enzyme involved in cholesterol trafficking, resulting in cholesterol accumulation in multiple organs
How do intracellular accumulations of proteins appear?
rounded, eosinophilic droplets, vacuoles, or aggregates in the cytoplasm
What condition are reabsorption droplets in proximal renal tubules seen in?
renal diseases associated with protein loss in the urine
When proteins accumulate and the ER becomes largely distended, what does the ER produce?
Russel Bodies = large, homogenous eosinophilic inclusions
What condition is associated with defective intracellular transport and secretion of critical proteins?
a1-antitrypsin deficiency; build up of partially folded intermediated that aggregate in the liver ER and deficiency of circulating enzymes leading to emphysema
What are some of the. cytoskeletal proteins that can build up?
- microtubules
- thin actin filaments
- thick myosin filaments
- intermediate filaments: keratin, neurofilaments, dessin filaments, vimentin filaments, glial filaments
What condition is associated with aggregation of abnormal proteins
amyloidosis
Hyaline change
homogenous, glassy, pink appearance
Examples of exogenous pigments
- carbon (coal dust): causes anthracosis in the lungs
- tattooing
Examples of endogenous pigments
- lipofuscin
- hemosiderin
- melanin
Lipofuscin
insoluble pigment composed of polymers of lipids and phospholipids in complex with protein; sign of free radical injury and lipid peroxidation; prominent in liver and heart of aging patients
Melanin
endogenous black pigment formed when tyrosinase catalyzes oxidation of tyrosine to dihydroxyphenylalanine in melanocytes (alkaptonuria)
Hemosiderin
hemoglobin derived, golden yellow to brown, granular or crystalline pigment that is one of the major storage forms of iron; when body breaks down heme into iron and biliverdin, the body traps the released iron in hemosiderin
Hemosiderosis
when there is a systemic overload of iron, hemosiderin deposits in organs and tissues
Causes: increased dietary iron absorption, hemolytic anemias, repeated blood transfusions
Pathologic calcification
abnormal tissue deposition of calcium salts with small amounts of iron, magnesium, and other mineral salts
Dystrophic calcification
when the deposition occurs locally in dying tissues
Metastatic calcification
results from hypercalcemia secondary to some disturbance in calcium metabolism
Causes: increased secretion of PTH (hyperparathyroidism), resorption of bone tissue, abnormal sensitivity to vitamin D, renal failure causing the retention of phosphate leading to secondary hyperparathyroidism
Psammoma bodies
single necrotic cells that constitute seed crystals and become encrusted by mineral deposits that form progressive outer layers in lamellate configurations
What is cellular aging the result of?
progressive decline in cellular function and viability caused by genetic abnormalities and accumulation of cellular and molecular damage due to effects of exposure to exogenous influences
DNA damage in aging
1) carcinogen exposure and sporadic erros
2) production of ROS
3) DNA damage
4) defective DNA repair
5) mutations
6) cellular aging
Werner syndrome
defective helices protein that is involved in DNA replication and repair; causes rapid accumulation of chromosomal damage leading to early aging
Cellular senescence in aging
1) cellular senescence (cells limited capacity for replication)
2) telomere shortening
3) decreased cellular replication
4) cell loss
5) cellular aging
What tumor suppressor proteins does CDKN2A encode?
p16 and INK4al control G1 to S phase progression during cell cycle
Defective protein homeostasis in aging
1) defective protein homeostasis
2) decreased proteins, increased damaged proteins
3) decreased cell functions
4) cellular aging
Rapamycin
inhibits mTOR pathway, increase life span, induces promotion of autophagy
IGF-1 signaling pathway
1) IGF-1 produced in response to growth hormone secretion by pituitary
2) mimics intracellular signaling by insulin and informs cells of the availability of glucose, promoting anabolic state
3) targets AKT and mTOR downstream
Sirtuins
NAD-dependents protein deacetylases that promote expression of genes whose products increase longevity (proteins that inhibit metabolic activity, reduce apoptosis, stimulate protein folding, inhibit harmful effects of oxygen free radicals); also increase insulin sensitivity and glucose metabolism
Role of caloric restriction on aging
reduces signaling intensity of IGF-1 pathway and increases sirtuins to overall increase longevity
