Tissue Hypoxia.pptxvvvvvvvvvvvvvvvvvvvvvvvvv

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1. Tissue Hypoxia

2. Hypoxia deprives the ETC of sufficient oxygen, decreasing the rate of ETC and ATP production When ATP levels fall, glycolysis increases and, in the absence of oxygen , will produce lactate (lactic acidosis ) In a myocardial infarction (MI), myocytes swell as the membrane potential collapses and the cell gets leaky. Enzymes are released from the damaged tissue, and lactic acidosis contributes to protein precipitation

3. Inhibitors The ETC is coupled to oxidative phosphorylation so that their activities rise and fall together. Inhibitors of any step effectively inhibit the whole coupled process, resulting in Decreased oxygen consumption Increased intracellular NADH/NAD and FADH2/FAD ratios Decreased ATP

4. Cyanide it binds irreversibly to cytochrome c oxidase( a Cu/ heme protein; cytochrome oxidase, complex IV), preventing electron transfer to oxygen Cyanide reacts with the ferric form of heme a 3 Sources of cyanide include: Burning polyurethane (foam stuffing in furniture and mattresses)

5. Nitrites may be used as an antidote for cyanide poisoning if given rapidly. They convert hemoglobin to methemoglobin, which binds cyanide in the blood before reaching the tissues. Oxygen is also given, if possible Carbon monoxide Carbon monoxide binds to cytochrome a / a 3 but less tightly than cyanide. It also binds to hemoglobin, displacing oxygen . Symptoms include headache, nausea, tachycardia , and tachypnea. Lips and cheeks turn a cherry-red color. Respiratory depression and coma result in death if not treated by giving oxygen

6. Sources of carbon monoxide include : Propane heaters and gas grills Vehicle exhaust Tobacco smoke House fires Methylene chloride–based paint strippers

7. Antimycin A interferes with electron flow from cytochrome b H in Q-cytochrome c oxidoreductase complex Other inhibitors include doxorubicin ( CoQ ), and oligomycin (F0).

8. Uncouplers Uncouplers are chemicals that decrease the proton gradient, causing: Decreased ATP synthesis Increased oxygen consumption Increased oxidation of NADH

9. Regulated Uncoupling This leads to generation of heat in the body in hibernating animals , in some newborn animals (including human beings), and in mammals adapted to cold . Brown adipose tissue, which is very rich in mitochondria (often referred to as brown fat mitochondria), is specialized for this process of nonshivering thermogenesis

10. UCP-1, or thermogenin forms a pathway for the flow of protons from the cytosol to the matrix In essence, UCP-1 generates heat by short-circuiting the mitochondrial proton battery . This dissipative proton pathway is activated by free fatty acids liberated from triacylglycerols in response to hormonal signals, such as b-adrenergic agonists

11. Other Important uncouplers include 2,4-dinitrophenol (2,4-DNP) and aspirin (and other salicylates ) Aspirin in doses used to treat rheumatoid arthritis can result in uncoupling of oxidative phosphorylation , increased oxygen consumption , depletion of hepatic glycogen , and the pyretic effect of toxic doses of salicylate. Depending on the degree of salicylate intoxication, the symptoms can vary from tinnitus to pronounced CNS and acid-base disturbance .

12. Reactive oxygen species Partial reduction of molecular oxygen leads to production of reactive species These react rapidly with lipids to cause peroxidation , with proteins, and with other substrates, resulting in denaturation and precipitation in tissues They include? Superoxide ( O2.–) Hydrogen peroxide (H2O2) Hydroxyl radical (OH.)

13. WBC produce these cells to kill bacteria in during phagocytosis Production of these same ROS can occur at a slower rate wherever there is oxygen in high concentration Small quantities of ROS are byproducts of ETC Large quantities are produced in reperfusion injury in a tissue that has been temporarily deprived of oxygen When oxygen is suddenly introduced, there is a burst of activity in the ETC , generating incompletely reduced ROS

14. The processes that adequately detoxify the superoxide require a variety of enzymes and compounds , including superoxide dismutase, catalase, as well as glutathione peroxidase, vitamin E in membranes, and vitamin C in the cytoplasm Low levels of any of these detoxifying substances result in hemolysis

15. Mitochondrial Diseases Leber hereditary optic neuropathy (LHON ) a form of blindness that strikes in midlife as a result of mutations to the NADH-Q oxidoreductase component of Complex I Some of these mutations impair NADH utilization, whereas others block electron transfer to Q The accumulation of mutations in mitochondrial genes in the course of several decades may contribute to aging, degenerative disorders, and cancer.

16. Key characteristics of most mitochondrial DNA ( mtDNA ) diseases are lactic acidosis and massive proliferation of mitochondria in muscle, resulting in ragged red fibers Others include; Mitochondrial encephalomyopathy , lactic acidosis, and stroke-like episodes(MELAS ) Ragged red muscle fiber disease