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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96 Fig. 8.1. Membrane damage drives turnover. The Mitochondrial Free Radical Theory of Aging means that, if cellular division is rapid enough, the SOS cycle will be short-circuited (see Fig. 8.3). There will be no significant digestion of mitochondria, because membrane damage is diluted as fast as it is inflicted. Mutant mtDNA will therefore not accumulate by this mechanism in tissues composed of such cell types. Only in non-dividing or rarely-dividing cell types will there be an accumulation of respiration-deficient mitochondria. 8.5.4. Why SOS Doesn’t Happen with ATPase Point Mutations Mutations that will be amplified according to SOS are ones that reduce the proton gradient. All mutations that abolish the function of respiratory chain will do this, whether they affect individual proteins or whether they mutate tRNAs and thus eliminate all 13 proteins. But mutations that affect only the ATPase subunits will have the opposite effect: they will have no effect on the creation of the gradient, only on its dissipation, so in fact the gradient would be predicted to rise slightly. Such mutations would thus be destroyed by SOS, rather than amplified. 8.6. Division as Autonomous Repair? The phenomenon of self-inflicted proton leak gave rise in 1990 to one more possible mechanism for preferential replication of mutant mtDNA, which is a great deal more consistent with the observed data than any of the models described earlier (Sections 8.1 and

The Search for How Mutant mtDNA is Amplified Fig. 8.2. Mutant mtDNA preferentially evades destruction. 8.2). Furthermore, it shares with SOS the additional advantage of providing an explanation for why mitochondrial turnover happens at all. I present it here, rather than with the other preferential replication-based models (see Sections 8.1 and 8.2), partly because I was unaware of it at the time I formulated SOS: it was proposed 6 only negatively, as a circumstantially unlikely alternative to the cis-regulation model. It must still be considered a candidate for the actual mechanism of clonal amplification of mutant mtDNA: there is some experimental evidence against it, but not enough (in my view) to rule it out quite yet. The essence of this idea is that the individual mitochondrion, not the cell, is the entity that controls the timing of its replication. There is proposed to be a pool of raw materials for mitochondrial replication available in the cytosol, which a mitochondrion imports when triggered to do so by some aspect of the intramitochondrial environment—most simply, shortage of matrix ATP. Shortage of ATP can be caused by self-inflicted proton leak, so mitochondrial replication in non-dividing cells will result. The role of lysosomal degradation is then at the tail of the causal chain, as the random destruction of mitochondria (irrespective of their integrity) when the cell simply has too many. In rapidly-dividing tissue, a mechanism for homeostasis is also available: cell division requires cell growth, which dilutes cytosolic ATP; intramitochondrial ATP is thus exported more rapidly, so intramitochondrial ATP 97

96<br />

Fig. 8.1. Membrane damage drives turnover.<br />

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

means that, if cellular division is rapid enough, the SOS cycle will be short-circuited (see<br />

Fig. 8.3). <strong>The</strong>re will be no significant digestion <strong>of</strong> mitochondria, because membrane damage<br />

is diluted as fast as it is inflicted. Mutant mtDNA will therefore not accumulate by this<br />

mechanism in tissues composed <strong>of</strong> such cell types. Only in non-dividing or rarely-dividing<br />

cell types will there be an accumulation <strong>of</strong> respiration-deficient mitochondria.<br />

8.5.4. Why SOS Doesn’t Happen with ATPase Point Mutations<br />

Mutations that will be amplified according to SOS are ones that reduce the proton<br />

gradient. All mutations that abolish the function <strong>of</strong> respiratory chain will do this, whether<br />

they affect individual proteins or whether they mutate tRNAs and thus eliminate all 13<br />

proteins. But mutations that affect only the ATPase subunits will have the opposite effect:<br />

they will have no effect on the creation <strong>of</strong> the gradient, only on its dissipation, so in fact the<br />

gradient would be predicted to rise slightly. Such mutations would thus be destroyed by<br />

SOS, rather than amplified.<br />

8.6. Division as Autonomous Repair?<br />

<strong>The</strong> phenomenon <strong>of</strong> self-inflicted proton leak gave rise in 1990 to one more possible<br />

mechanism for preferential replication <strong>of</strong> mutant mtDNA, which is a great deal more<br />

consistent with the observed data than any <strong>of</strong> the models described earlier (Sections 8.1 and

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