The Mitochondrial Free Radical Theory of Aging - Supernova: Pliki
The Mitochondrial Free Radical Theory of Aging - Supernova: Pliki The Mitochondrial Free Radical Theory of Aging - Supernova: Pliki
130 The Mitochondrial Free Radical Theory of Aging enzymes then remove this chain and replace it with a new one.) But it has the peculiar property that it preferentially detaches side chains that have been oxidized. It is particularly good at this because the chain that it removes, the one attached to the middle of the three carbons that make up the phospholipid’s glycerol core, is the one that is most often polyunsaturated (and thus oxidisable). In this way, phospholipase A2 keeps the level of membrane oxidation down. 51,52 But it doesn’t keep it constant. The property that makes enzymes so very useful in cells is, in this case, a weakness: their specificity. Here, phospholipase A2 can excise oxidized fatty acid side chains, but only if the oxygen has been incorporated in a place in the molecule that the enzyme can recognise. Lipid peroxidation involves the creation of innumerable varieties of oxidized carbon chain (see Section 3.8), and some of them do not fit the template that phospholipase A2 recognises. Of course there may be other, parallel systems that do the same job as phospholipase A2 but on different oxidation products; but still there will be some molecules that none of the systems recognises. If you doubt this, think about lipofuscin. It accumulates in cells during life, and is the indigestible remnant of oxidatively modified lipid and protein; and there we are talking about indigestibility inside a lysosome, where there is a far greater repertoire of destructive enzymes than exists in the cytosol. It is clear, therefore, that a significant subset of the undesirable molecules generated by lipid peroxidation will accumulate in mitochondrial membranes until such time as their cumulative effect causes the mitochondrion to fail, and so to be engulfed by a lysosome, or else to be replicated, diluting the damage. 10.11. How Can SOS Explain mtDNA Depletion? In Section 6.6 I mentioned that the single-cell analyzes of Müller-Höcker showed that some cells appeared to lose all their mtDNA, not just to become taken over by mutant copies. 53 It is not possible to establish this by looking at enzymatic activity, because the loss of all the mtDNA is functionally equivalent to the mutation of a tRNA—either way, all the 13 proteins cease to be constructed. But several of Müller-Höcker’s studies involved staining of the DNA itself, not the protein products. It is still completely unknown how mtDNA replication is regulated, but we can be sure that the regulation is quite tightly coupled to mitochondrial division. Human mitochondria have about five copies of the mtDNA on average, and this number must be doubled with each mitochondrial division. The copies are partitioned between the two daughter mitochondria. It seems intuitively likely that this partitioning is not always quite accurate, so that perhaps one mitochondrion occasionally ends up with, say, only two copies of the mtDNA. But that should be no problem at all for it, because it can quickly replicate those copies in order to restore its DNA complement to the normal. So mitochondria which undergo this temporary, partial depletion should not be distinguished, during subsequent mitochondrial turnover, from ones which do not. But there is inevitably a possibility, albeit maybe only a very small one, that a dividing mitochondrion will get the partitioning completely wrong and create a daughter mitochondrion which has no copies of the mtDNA at all. If that happens, then clearly such a daughter cannot haul itself back to normal by mtDNA replication. If it is lucky enough to undergo fusion with another mitochondrion (one which, typically, still has mtDNA) then it will be restored; but, as noted in Section 10.8, fusion seems to be rather rare. And until and unless that happens, it will have exactly the same behaviour—and selective advantage—as a mitochondrion which has (for example) mutated a tRNA in all copies of its mtDNA. This therefore provides a possible mechanism for the occurrence of cells whose mitochondria are completely lacking in mtDNA. The mispartitioning need only occur less
Frequently-Asked Questions Fig. 10.3. How average subthreshold LDL oxidation (arrows) varies with its overall oxidation. than once in a billion mitochondrial divisions in order to give rise to the observed frequency of such cells, so I believe that this is a plausible and parsimonious explanation. 10.12. Why Isn’t Longevity Mainly Maternally Inherited? Since mtDNA is almost all maternally inherited, if mtDNA damage drives the rate of aging then the inherited component of longevity might also be expected to be maternally inherited. Three answers are popular; hence they will all be summarized here, even though (as will be seen) only the third really answers the question directly. Answer 1 is that possibly there is a bias—a greater maternal than paternal contribution to longevity. 54,55 However, no one currently claims that the maternal contribution is, say, 90% of the total. Answer 2 is that there is no bias because the mitochondrial DNA is not what matters in mitochondrial decline. This view is becoming popular, but it is not really valid to call it the mitochondrial theory of aging. The idea is that the decline in mitochondrial function results from increased oxidative stress, which (by unknown mechanisms) affects the composition of the mitochondrial membrane, and in turn (probably) the efficacy of the respiratory chain. This idea is very strongly supported by recent work. 56a However, it says nothing about where the oxidative stress comes from in the first place, whereas MiFRA says that damage to 131
- Page 85 and 86: History of the Mitochondrial Free R
- Page 87 and 88: History of the Mitochondrial Free R
- Page 89 and 90: History of the Mitochondrial Free R
- Page 91 and 92: CHAPTER 7 The Status of Gerontologi
- Page 93 and 94: The Status of Gerontological Theory
- Page 95 and 96: The Status of Gerontological Theory
- Page 97 and 98: CHAPTER 8 The Search for How Mutant
- Page 99 and 100: The Search for How Mutant mtDNA is
- Page 101 and 102: The Search for How Mutant mtDNA is
- Page 103 and 104: The Search for How Mutant mtDNA is
- Page 105 and 106: The Search for How Mutant mtDNA is
- Page 107 and 108: CHAPTER 9 The Search for How So Few
- Page 109 and 110: The Search for How So Few Anaerobic
- Page 111 and 112: The Search for How So Few Anaerobic
- Page 113 and 114: The Search for How So Few Anaerobic
- Page 115 and 116: The Search for How So Few Anaerobic
- Page 117 and 118: The Search for How So Few Anaerobic
- Page 119 and 120: The Search for How So Few Anaerobic
- Page 121 and 122: CHAPTER 10 Frequently-Asked Questio
- Page 123 and 124: Frequently-Asked Questions The effe
- Page 125 and 126: Frequently-Asked Questions Table 10
- Page 127 and 128: Frequently-Asked Questions through
- Page 129 and 130: Frequently-Asked Questions has been
- Page 131 and 132: Frequently-Asked Questions SOS, sin
- Page 133 and 134: Frequently-Asked Questions for almo
- Page 135: Frequently-Asked Questions Fig. 10.
- Page 139 and 140: Frequently-Asked Questions of elect
- Page 141 and 142: Frequently-Asked Questions Referenc
- Page 143 and 144: Frequently-Asked Questions 45. Clay
- Page 145 and 146: CHAPTER 11 A Challenge from Textboo
- Page 147 and 148: A Challenge from Textbook Bioenerge
- Page 149 and 150: A Challenge from Textbook Bioenerge
- Page 151 and 152: A Challenge from Textbook Bioenerge
- Page 153 and 154: A Challenge from Textbook Bioenerge
- Page 155 and 156: A Challenge from Textbook Bioenerge
- Page 157 and 158: A Challenge from Textbook Bioenerge
- Page 159 and 160: A Challenge from Textbook Bioenerge
- Page 161 and 162: A Challenge from Textbook Bioenerge
- Page 163 and 164: A Challenge from Textbook Bioenerge
- Page 165 and 166: 160 The Mitochondrial Free Radical
- Page 167 and 168: 162 The Mitochondrial Free Radical
- Page 169 and 170: 164 The Mitochondrial Free Radical
- Page 171 and 172: 166 The Mitochondrial Free Radical
- Page 173 and 174: 168 The Mitochondrial Free Radical
- Page 175 and 176: 170 The Mitochondrial Free Radical
- Page 177 and 178: CHAPTER 14 Ablation of Anaerobic Ce
- Page 179 and 180: Ablation of Anaerobic Cells: Techni
- Page 181 and 182: CHAPTER 15 Transgenic Copies of mtD
- Page 183 and 184: Transgenic Copies of mtDNA: Techniq
- Page 185 and 186: Transgenic Copies of mtDNA: Techniq
Frequently-Asked Questions<br />
Fig. 10.3. How average subthreshold LDL oxidation (arrows) varies with its overall oxidation.<br />
than once in a billion mitochondrial divisions in order to give rise to the observed frequency<br />
<strong>of</strong> such cells, so I believe that this is a plausible and parsimonious explanation.<br />
10.12. Why Isn’t Longevity Mainly Maternally Inherited?<br />
Since mtDNA is almost all maternally inherited, if mtDNA damage drives the rate <strong>of</strong><br />
aging then the inherited component <strong>of</strong> longevity might also be expected to be maternally<br />
inherited. Three answers are popular; hence they will all be summarized here, even though<br />
(as will be seen) only the third really answers the question directly.<br />
Answer 1 is that possibly there is a bias—a greater maternal than paternal contribution<br />
to longevity. 54,55 However, no one currently claims that the maternal contribution is, say,<br />
90% <strong>of</strong> the total.<br />
Answer 2 is that there is no bias because the mitochondrial DNA is not what matters in<br />
mitochondrial decline. This view is becoming popular, but it is not really valid to call it the<br />
mitochondrial theory <strong>of</strong> aging. <strong>The</strong> idea is that the decline in mitochondrial function results<br />
from increased oxidative stress, which (by unknown mechanisms) affects the composition<br />
<strong>of</strong> the mitochondrial membrane, and in turn (probably) the efficacy <strong>of</strong> the respiratory chain.<br />
This idea is very strongly supported by recent work. 56a However, it says nothing about where<br />
the oxidative stress comes from in the first place, whereas MiFRA says that damage to<br />
131
Change language