The Mitochondrial Free Radical Theory of Aging - Supernova: Pliki
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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

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74 The Mitochondrial Free Radical Theory of Aging Fig. 6.2. A hypothesis for why longer-lived homeotherms make less enzymatic antioxidants. 6.6. Amplification of Mutant mtDNA; Demise of the Vicious Cycle Theory The last of the experimental breakthroughs which underpin the modern mitochondrial free radical theory of aging was due to a number of researchers; foremost among these was Josef Müller-Höcker, working in Munich. He concentrated on studies of intact tissue samples,

History of the Mitochondrial Free Radical Theory of Aging, 1954-1995 most often muscle, which he analyzed in various ways—with DNA probes, with antibodies, or with enzymatic assays—in order to identify the distribution of certain mitochondrial defects. He made two pivotal discoveries. The first of these was that the loss of mitochondrial function which others had detected was not distributed evenly across the tissue, but was localised in just a few cells or muscle fibres, and that these fibres (actually, as it turned out, short segments of them) were totally devoid of aerobic respiration. 54 Even stranger was that he only occasionally detected fibres in which the level of respiration was reduced but non-zero. 54,55 This showed that, if the vicious cycle theory was correct, then (a) it went on in each cell independently of its neighbours, and (b) it was very, very vicious. Cells independently, for whatever reason, reached a point where the cycle took off; after that, they must plummet to aerobic oblivion in (at most) a matter of months, or else we would catch more of them in the act of plummeting.* The second, and even more important, observation came when he assayed the same sample of muscle with two different mtDNA probes. 57 He found that the cells which were completely lacking in respiration were lacking for genetically different reasons. In one such cell there would be almost complete loss of hybridisation to one probe but absolutely normal reaction with the other, while in another cell it would be the opposite way around. Some cells had lost affinity for both probes; some had lost neither (indicating a mutation elsewhere). This meant that the vicious cycle theory had to be radically revised. It was no longer possible to say that stress caused more mtDNA mutations causing more stress, because a cycle like that would necessarily give a virtually identical spectrum of mutations in each and every affected cell, irrespective of which ones were present first in a given cell. We see the exact opposite—each cell taken over by, ostensibly, just one mutation. (A single mutation was able to remove both probed regions in Müller-Höcker’s experiments, by being a large deletion or a complete loss of the whole mtDNA (mtDNA depletion, of which more in Section 10.11); in histochemical assays the same effect would also result from mutation of a mitochondrial tRNA gene.) This meant that there was not an intracellular vicious cycle—at least, not at the level of mtDNA mutation. Rather, the cell was somehow allowing its mitochondrial population to be taken over by copies of a single initial mutation: the mutant molecule was somehow experiencing a selective advantage. It is appropriate—and salutory—at this point to take a brief leap back in time. In 1974, just two years after Harman had suggested the involvement of mitochondria in the free radical theory, Comfort 58 identified the existence of mitochondrial turnover as a serious challenge to that possibility. He reasoned that damaged mitochondria would obviously be got rid of and replaced by functional ones, so damage could never accumulate. He was wrong, but his point that mutant and wild-type mitochondria have independent propensities to be maintained in the cell—they compete, effectively—was key. In hindsight, it is highly unlikely that the two genotypes will be exactly equally matched in this context, so one or other will inevitably win out; since we see an accumulation of mutant mtDNA, we should have immediately expected that it would be caused mainly by clonal amplification. Yet this idea was not picked up on for twenty years. *Another way, not involving intact tissue samples, in which it was established that mutations are not distributed evenly across all cells is to analyse the DNA of only a few cells. If a homogenate of many thousands of muscle fibres is analysed, it is found always to contain the “common deletion” (see Section 2.4.5) at levels around 0.1%. If the same sample is divided into small bundles of only ten fibres, however, nearly all the bundles show no evidence of the deletion whereas one or two show high concentrations of it. 56 75

74<br />

<strong>The</strong> <strong>Mitochondrial</strong> <strong>Free</strong> <strong>Radical</strong> <strong>The</strong>ory <strong>of</strong> <strong>Aging</strong><br />

Fig. 6.2. A hypothesis for why longer-lived homeotherms make less enzymatic antioxidants.<br />

6.6. Amplification <strong>of</strong> Mutant mtDNA; Demise <strong>of</strong> the Vicious Cycle<br />

<strong>The</strong>ory<br />

<strong>The</strong> last <strong>of</strong> the experimental breakthroughs which underpin the modern mitochondrial<br />

free radical theory <strong>of</strong> aging was due to a number <strong>of</strong> researchers; foremost among these was<br />

Josef Müller-Höcker, working in Munich. He concentrated on studies <strong>of</strong> intact tissue samples,

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