The Mitochondrial Free Radical Theory of Aging - Supernova: Pliki

An Introduction to Mitochondria
2.4.5. The Vulnerability of mtDNA and Mitochondrial Function
The 13 proteins encoded in the mtDNA are absolutely essential for OXPHOS to occur.
It is therefore just as important for an organism to maintain its mtDNA intact (in all cells,
not simply the germ line) as to maintain its nuclear, chromosomal DNA. However, for reasons
connected with mitochondria’s evolutionary origin (which was described in Section 2.1),
cells fail to maintain their mtDNA to the nuclear standard. The mtDNA is much more
prone to suffer spontaneous changes to its sequence, which result in the production of
incorrect or truncated proteins—or, in some cases, failure to produce any protein at all.
This vulnerability takes several forms. Firstly, the mtDNA is much more exposed than
the nuclear DNA to free radicals that can induce mutations. This is because mitochondria
are the main cellular site of production of free radicals; this will be explained in Section 3.3.
There are no mitochondria in the nucleus, so the nuclear DNA is exposed to a much lower
concentration of free radicals.
A second source of mtDNA vulnerability is that it is “naked.” Nuclear DNA is always
wrapped around special proteins called histones, which keep it somewhat protected from
mutagenic attack. mtDNA does not have these. 60
Another reason is that, once damage is done to it, mtDNA is less well repaired than
nuclear DNA. Certain classes of damage to DNA are rapidly reversed when they occur in the
nucleus, but do not get mended in mitochondria. For some years it was believed that mtDNA
was not repaired at all, but this was a piece of bad luck: the first researchers to address this
question 61 had happened to analyse a class of damage called a pyrimidine dimer,* which
indeed is not repaired at all in mtDNA, and most investigators incorrectly presumed that
this was true of other types of damage too.
Yet another problem for mtDNA is that it contains a high level of short sequences
which appear twice, some way apart. This is dangerous, because it is possible for the circular
mtDNA molecule to wrap around into a figure of eight, with the two identical sequences
lying next to each other. When that happens, there is occasionally a “crossover”—the strands
come apart and join up the other way, just as chromosomes do in meiosis. For a mtDNA
molecule, however, this is fatal, because the single circle of DNA becomes two circles, each
with only a subset of the necessary genetic material (see Fig. 2.11). Worse yet, one of those
two circles will be without the D loop, a small stretch of DNA which contains no genes but
which is essential for initiating replication of the molecule. Thus, the circle without the D
loop will never be replicated and will eventually be lost, so that the final result is a deletion
of a large chunk of the mtDNA. Indeed, these are easily detected in humans in vivo. In
theory, the longer the stretch of duplicated sequence the greater will be the tendency for this
to occur. In practice, one particular deletion is much more prevalent than any other 62a —so
* The four nucleotides that endow DNA with its informational content are classified into two sets of two, on
account of their atomic structure. Cytosine and thymine are pyrimidines, with a single-ring structure;
adenine and guanine are purines, which have a double-ring structure. Thus, the complementary bases on
opposite strands of the double helix are always one pyrimidine and one purine. The other discriminant,
which causes (e.g.) adenine always to be paired with thymine rather than with cytosine, is that adenine and
thymine are prone to form two hydrogen bonds whereas guanine and cytosine form three (see Fig. 2.10). A
pyrimidine dimer is the result of a covalent bond being formed between adjacent pyrimidines on the same
strand.
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