Cellular responses to stress (Adaptations, injury and death)

(5 of 5)

**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

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

Now we will discuss 3 topics related to cell injury

• Intracellular accumulations

• Extracellular deposition of calcium

• Aging

INTRACELLULAR ACCUMULATIONS

• Fatty Change (Steatosis)

• Cholesterol and Cholesteryl Esters

• Proteins

• Glycogen

• Pigments: -Carbon

-Lipofuscin (wear-and-tear pigment)

-Melanin

-Hemosiderin

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

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

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

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

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)

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

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:

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

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

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?

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?

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

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?

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

Decreased replication, cont’d

• Telomerase activity:

-in germ cells

-in low levels in stem cells

-absent in most somatic cells

-reactivated in cancer cells

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

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