The Mitochondrial Free Radical Theory of Aging - Supernova: Pliki

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An Introduction to Lipid Metabolism Fig. 4.2. Cholesterol. because it can be used as fuel for the TCA cycle (which is always needed), so homeostasis is achieved by regulating the uptake and storage of the TCA cycle’s other main fuel, glucose. 4.3. Good and Bad LDL The blood stream is used as a transporter not only of cholesterol but of all nutrients, so it is not an especially predictable environment. LDL and HDL particles can, in particular, suffer chemical changes during their journey which can, potentially, render them toxic to the cells that are their intended destination. The main such modification is oxidation. In the case of HDL, this is not much of a problem, because the destination cells (in the liver) are purpose-built to deal with all manner of toxins and are not likely to suffer unduly. The situation with LDL is much more serious. We know that LDL particles can undergo modifications that make them toxic to most cells, not only because of in vitro experiments 9 but also because of the extreme care that the body takes to avoid this damage. Firstly, the intracellular machinery that imports LDL specifically rejects (fails to bind) LDL that has been significantly oxidized. 10 Secondly, a certain type of white blood cell called a monocyte has the potential to turn into a vacuum cleaner for oxidized LDL, by attaching itself to the artery wall and expressing a different type of surface protein that imports oxidized LDL even more assiduously than unoxidized. 11 (We will consider a highly deleterious side-effect of this process—atherosclerosis—in Section 5.1.) Thirdly, the blood contains high levels of various chemicals that limit the rate at which LDL oxidation occurs in the first place; these will also be discussed in detail later. There is, however, a major paradox concerning the presence of oxidized LDL in the blood stream. It was shown in 1984 12 that the oxidation of LDL by cultured cells is totally abolished by the addition to the culture medium of antioxidants such as vitamin E, and moreover that the concentration one needed to add was a good deal less than is present in the blood stream. The same is true of the arterial intima. 13 Thus, ostensibly, LDL oxidation should not be happening in the body at all! The only way out of this is to presume the existence of oxidation “hot spots” in the extracellular medium, in which the concentration of toxins (such as LECs) is much higher than average and/or that of antioxidants is much lower. No such non-uniformity has been identified experimentally, but a possible one will be described in Chapter 9; see also Section 10.13. 51
52 The Mitochondrial Free Radical Theory of Aging References 1. Paradies G, Ruggiero FM. Age-related changes in the activity of the pyruvate carrier and in the lipid composition in rat-heart mitochondria. Biochim Biophys Acta 1990; 1016:207-212. 2. Paradies G, Ruggiero FM, Petrosillo G et al. Age-dependent decline in the cytochrome c oxidase activity in rat heart mitochondria: Role of cardiolipin. FEBS Lett 1997; 406:136-138. 3. Chang TY, Telakowski C, Heuvel WV et al. Isolation and partial characterization of a cholesterol-requiring mutant of Chinese hamster ovary cells. Proc Natl Acad Sci USA 1977; 74:832-836. 4. Sagawa S, Shiraki K. Changes of osmotic fragility of red blood cells due to repletion or depletion of cholesterol in human and rat red cells in vitro. J Nutr Sci Vitaminol (Tokyo) 1980; 26:161-169. 5. Holmes R, Helms J, Mercer G. Cholesterol requirement of primary diploid human fibroblasts. J Cell Biol 1969; 42:262-271. 6. Tall AR. An overview of reverse cholesterol transport. Eur Heart J Suppl A 1998; 19:A31-A35. 7. Chisolm GM. The oxidation of lipoproteins: Implications for atherosclerosis. In: Sies H, ed. Antioxidants in disease: Mechanisms and therapy. San Diego: Academic Press, 1997:88-106. 8. Trigatti BL, Gerber GE. A direct role for serum albumin in the cellular uptake of long-chain fatty acids. Biochem J 1995; 308:155-159. 9. Hessler JR, Morel DW, Lewis LJ et al. Lipoprotein oxidation and lipoprotein-induced cytotoxicity. Arteriosclerosis 1983; 3:215-222. 10. Mahley RW, Innerarity TL, Pitas RE et al. Inhibition of lipoprotein binding to cell surface receptors of fibroblasts following selective modification of arginyl residues in arginine-rich and B apoproteins. J Biol Chem 1977; 252:7279-7287. 11. Henriksen T, Mahoney EM, Steinberg D. Enhanced macrophage degradation of biologically modified low density lipoprotein. Arteriosclerosis 1983; 3:149-159. 12. Steinbrecher UP, Parthasarathy S, Leake DS et al. Modification of low density lipoprotein by endothelial cells involves lipid peroxidation and degradation of low density lipoprotein phospholipids. Proc Natl Acad Sci USA 1984; 81:3883-3887. 13. Dabbagh AJ, Frei B. Human suction blister interstitial fluid prevents metal ion-dependent oxidation of low density lipoprotein by macrophages and in cell-free systems. J Clin Invest 1995; 96:1958-1966.
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COMPANY de Grey The Mitochondrial F
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7. The Status of Gerontological The
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The Search for How So Few Anaerobic
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Frequently-Asked Questions The effe
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Frequently-Asked Questions Fig. 10.
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Frequently-Asked Questions Referenc
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Frequently-Asked Questions 45. Clay
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CHAPTER 11 A Challenge from Textboo
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CHAPTER 14 Ablation of Anaerobic Ce
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Ablation of Anaerobic Cells: Techni
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CHAPTER 15 Transgenic Copies of mtD
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Index Symbols “~”, 19 A Acetald
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