1. Cellular responses to stress (Adaptations, injury and death) (5 of 5)
Ali Al Khader, MD
Faculty of Medicine
Al-Balqa’ Applied University

2. **Autophagy (“self-eating”)**
= lysosomal digestion of the cell’s own components *Used in times of nutrient deprivation …also for clearance of misfolded proteins…e.g., when abnormal: neurodegenerative disorders may result *Autophagy genes (Atg genes) are activated *Organelles + portions of cytosol sequestered within an autophagic vacuole

3. Autophagy, cont’d
Autophagic vacuole formed from ribosome-free regions of the ER
Vacuole fuses with lysosome autophagolysosome
With more severe deprivation autophagy can signal apoptosis
Polymorphisms in autophagy genes are associated with inflammatory bowel disease…by unknown mechanisms

4. Now we will discuss 3 topics related to cell injury
Intracellular accumulations
Extracellular deposition of calcium
Aging

5. INTRACELLULAR ACCUMULATIONS
Fatty Change (Steatosis)
Cholesterol and Cholesteryl Esters
Proteins
Glycogen
Pigments: -Carbon
-Lipofuscin (wear-and-tear pigment)
-Melanin
-Hemosiderin

6. Fatty Change (Steatosis)
= accumulation of triglycerides in parenchymal cells
Liver is the most common organ. Why?
May also occur in heart, skeletal muscle, and others
Causes: -toxins
-protein malnutrition
-diabetes mellitus
-obesity
-anoxia
The most common causes of fatty liver are: -alcohol
-DM associated with obesity

7. Cholesterol and Cholesteryl Esters
Cholesterol metabolism is important for membrane synthesis
Accumulation of lipids (triglycerides, cholesterol, and cholesteryl esters) in phagocytic cells:
….different pathologic processes, and atherosclerosis is the most
important example

8. Proteins Much less common than lipid accumulations Examples:
-Kidney: -normally trace amounts of albumin are filtered through the
glomerulus and reabsorbed by pinocytosis in the proximal
convoluted tubules, but in nephrotic syndrome:
Heavy proteinuria reabsorption of protein vesicles
accumulate
…on H&E: pink, hyaline cytoplasmic droplets
…the process is reversible

9. Other examples of protein accumulation
Immunoglobulins in the RER of some plasma cells
…rounded, eosinophilic bodies called:
Alcoholic hyaline in the liver
Neurofibrillary tangles in neurons

10. Glycogen Abnormalities in the metabolism of either glucose or glycogen
Examples: -DM: glycogen accumulates in:
-renal tubular epithelium
-cardiac myocytes
-β cells of the islets of Langerhans
-Glycogen storage diseases (glycogenoses)

11. Pigments Exogenous or synthesized in the body
Carbon (an example is coal dust)…anthracosis…the most common exogenous pigment
Lipofuscin, or “wear-and-tear pigment”…in heart, liver and brain
…due to aging or atrophy
= complexes of lipid and protein that derive from the free radical–
catalyzed peroxidation of polyunsaturated lipids of subcellular
membranes
*not injurious, but marker of previous free radical injury
*What is brown atrophy?
*perinuclear electron-dense granules on EM

12. Pigments, cont’d Melanin: can also be accumulated in: -keratinocytes
-macrophages
Hemosiderin: hemoglobin-derived granular pigment
…local or systemic excess of iron (most of the time pathological)
…in cells, iron + apoferritin = ferritin micelles (stored as this)
…hemosiderin = large aggregates of ferritin micelles
…appears on LM (golden yellow to brown)
…special stain for iron: Prussian blue
…small amounts of this pigment are normal in the mononuclear phagocytes
of the bone marrow, spleen, and liver, where aging red cells are normally
degraded
…Excessive deposition of hemosiderin = hemosiderosis…hereditary disease with this is called:

13. PATHOLOGIC CALCIFICATION
= abnormal deposition of calcium salts, together with smaller amounts of iron, magnesium, and other minerals
Dystrophic calcification: in dying tissues
…no derangements in calcium metabolism (i.e., with normal
serum levels of calcium)
Metastatic calcification: in normal tissues-derangement in calcium metabolism-hypercalcemia
Note: hypercalcemia can exacerbate dystrophic calcification

14. Dystrophic Calcification
Areas of necrosis
Atheromas
May be incidental finding due to insignificant injury
May be harmful as in valve calcification due to aging
Pathogenesis:
-initiation (nucleation) extra- or intracellular
-propagation
…the ultimate end product: crystalline calcium phosphate

15. Dystrophic Calcification, cont’d
Initiation: first in extracellular vesicles derived from dying cells, where there is affinity of calcium for membranes phospholipids
…then phosphates are concentrated due to the action of membrane-
bound phosphatases
…intracellular accumulation starts in the mitochondria of dying cells
Propagation of crystal formation depends on:
-concentration of Ca2+ and PO4−
-the presence of mineral inhibitors
-the degree of collagenization… or crystal formation?

16. Metastatic Calcification
Causes of hypercalcemia:
-Hyperparathyroidism, like parathyroid tumors or paraneoplastic
syndromes (some tumors secrete parathyroid hormone–related protein)
-Destruction of bone due to:
-accelerated turnover (e.g., Paget disease)
-immobilization
-tumors (increased bone catabolism associated with multiple
myeloma, leukemia, or diffuse skeletal metastases)
-Vitamin D–related disorders:
-vitamin D intoxication
-sarcoidosis (in which macrophages activate a vitamin D precursor)
-Renal failure (secondary hyperparathyroidism)
due to?

17. CELLULAR AGING Aging starts at the level of the cell
Aging is the strongest independent risk factors for:
-cancer
-Alzheimer disease
-ischemic heart disease
-…etc.
Mechanisms:
-DNA damage
-Decreased replication
-Defective protein homeostasis

18. Decreased replication
All normal cells have a limited capacity for replication
…after a fixed number of divisions cells become arrested in a
terminally nondividing state, known as replicative senescence
…with old age: progressive replicative senescence
Werner syndrome: premature aging
by progressive shortening of telomeres
…What are telomeres?

19. Decreased replication, cont’d
As the telomeres become shorter, the ends of chromosomes cannot be protected and are seen as broken DNA, which signals cell cycle arrest
Telomere length is maintained by nucleotide addition by telomerase
a specialized RNA-protein complex that uses its own RNA as a template for adding nucleotides to the ends of chromosomes

20. Decreased replication, cont’d
Telomerase activity:
-in germ cells
-in low levels in stem cells
-absent in most somatic cells
-reactivated in cancer cells

21. Defective protein homeostasis
translation of proteins important for protein synthesis, with in
protein turnover
Defective activity of chaperones, proteasomes and repair enzymes
destroy misfolded proteins

22. Counteracting age process
insulin-like growth factor signaling
activation of kinases (esp., TOR (target of rapamycin) and AKT kinase)
Improved DNA repair
Improved protein homeostasis
Enhanced immunity
Proteins of the Sirtuin family, e.g., Sir2…deacetylate (activate) DNA repair enzymes