P-450 in the smooth ER of the liver and other organs. Although the metabolites might cause membrane damage and cell injury by direct covalent binding to protein and lipids, the most important mechanism of cell injury involves the formation of free radicals. Carbon tetrachloride (CCl4)—once widely used in the dry cleaning industry but now banned—and the analgesic acetaminophen belong in this category. The effect of CCl4 is still instructive as an example of chemical injury. CCl4 is converted to a toxic free radical, principally in the liver, and this free radical is the cause of cell injury, mainly by membrane phospholipid peroxidation. In less than 30 minutes after exposure to CCl4, there is sufficient damage to the ER membranes of hepatocytes to cause a decline in the synthesis of enzymes and plasma proteins; within 2 hours, swelling of the smooth ER and dissociation of ribosomes from the RER have occurred. There also is decreased synthesis of apoproteins that form complexes with triglycerides and thereby facilitate triglyceride secretion; this defect results in the accumulation of lipids in hepatocytes and other cells and the “fatty liver” of CCl4 poisoning. Mitochondrial injury follows, and subsequently diminished ATP stores result in defective ion transport and progressive cell swelling; the plasma membranes are further damaged by fatty aldehydes produced by lipid peroxidation in the ER. The end result can be cell death.
The accumulation of misfolded proteins in a cell can stress compensatory pathways in the ER and lead to cell death by apoptosis. During normal protein synthesis, chaperones in the ER control the proper folding of newly synthesized proteins, and misfolded polypeptides are ubiquitinated and targeted for proteolysis. If unfolded or misfolded proteins accumulate in the ER, they first induce a protective cellular response that is called the unfolded protein response (
Fig. 2.18 ). This adaptive response activates signaling pathways that increase the production of chaperones and decrease protein translation, thus reducing the levels of misfolded proteins in the cell. When a large amount of mis-folded protein accumulates and cannot be handled by the adaptive response, the signals that are generated result in activation of proapoptotic sensors of the BH3-only family as well as direct activation of caspases, leading to apoptosis by the mitochondrial (intrinsic) pathway.
Intracellular accumulation of misfolded proteins may be caused by abnormalities that increase the production of misfolded proteins or reduce the ability to eliminate them. This may result from gene mutations that lead to the production of proteins that cannot fold properly; aging, which is associated with a decreased capacity to correct misfolding; infections, especially viral infections, when large amounts of microbial proteins are synthesized within cells, more than the cell can handle; increased demand for secretory proteins such as insulin in insulin-resistant states; and changes in intracellular pH and redox state. Protein misfolding is thought to be the fundamental cellular abnormality in several neurodegenerative diseases (Chapter 23). Deprivation of glucose and oxygen, as in ischemia and hypoxia, also may increase the burden of misfolded proteins.
http://ebooksmedicine.net 46CHAPTER 2 Cell Injury, Cell Death, and Adaptations
Sensor of misfolded proteins (e.g., IRE1) Signaling Signaling
Cytosol Increased Reduced Increased Activation of Activation ofsynthesis of protein protein BH3 proteins caspaseschaperones synthesis degradation
Reduced load of misfolded proteins
ADAPTIVE TERMINAL UNFOLDED PROTEIN UNFOLDED PROTEIN RESPONSE RESPONSE: APOPTOSIS