The Mitochondrial Free Radical Theory of Aging - Supernova: Pliki

An Introduction to Mitochondria
The journey of nuclear-coded proteins whose eventual destination is not the matrix
but the inner membrane (or, in a few cases such as cytochrome c, the intermembrane space)
is rather more heterogeneous. Some of them have no signal sequence and pass only through
the outer membrane. 44 Others have two signal sequences of the sort described above: one
which causes them to be imported completely into the matrix, and another (which is invisible
to the relevant machinery until the first has been cleaved) that directs it part of the way out
again. 45 Yet others also have two, but the second acts as a barrier to import, so that the
mature protein stays in the intermembrane space even though the primary signal sequence
penetrates into the matrix (where it is chopped off). 46 A few inner membrane proteins,
particularly the carriers of anions such as ATP and phosphate, appear to find their way to
mitochondria despite having no presequence, but they have been presumed to use the same
pathway, because they were found to have internal sequences which are characteristic of
standard presequences, so may fold into a hairpin-like shape that makes the internal sequence
look like a presequence. 47 Quite recently, this has been elucidated in more detail: 48,49 these
anion carrier proteins do indeed use broadly the same “Tom” machinery to get across the
outer membrane, but they use a different “Tim” machinery, which embeds them in the
inner membrane from the outside, rather than diverting them into the matrix. The varieties
of mitochondrial protein import are depicted in Figure 2.9.
2.4.4. Curiosities of mtDNA
The mtDNA of many species has been studied and sequenced. In animals it is always
tiny: in humans, for example, it comprises only 16,569 base pairs, 40 of which virtually
every one is necessary for its function. In most plants and fungi, however, it is much larger,
containing large introns and other “junk DNA.” 50 This indicates that there has been
considerable evolutionary pressure for conciseness of mtDNA in animals, but sometimes
less elsewhere. We do not know the basis for this difference. In fact it may be somewhat less
dramatic than it seems, because the compactness of animal mtDNA is permitted mainly
by a single trick—the use of transfer RNA sequences as sites for chopping-up of a primary
transcript of almost the whole genome into separate RNAs for each of the proteins—which
relieves it of the need for any of the regulatory, untranslated sequence present in fungal
and plant mtDNA. 51,52
One rather surprising thing about the mtDNA is that it exists at all, since ostensibly it is
a major and unnecessary inconvenience. There is no formal need for it, because (as just
noted) cells have a system for getting proteins into mitochondria even when they are encoded
on nuclear genes: they are constructed in the usual way by ribosomes in the cytoplasm, and
then they are transported to a mitochondrion and hauled through its membranes. Reasons
why it has not been evolved away are explored in Section 10.2.
But even more surprising was the discovery 53,54 that mitochondrial DNA—again, in
animals but not plants—has a different genetic code than the nuclear DNA. The process of
turning a sequence of nucleotides into a sequence of amino acids involves the recognition
of triplets of nucleotides as coding for a particular amino acid, or else for “this is the end of
the protein.” Since there are four different nucleotides, there are 4 3 = 64 possible triplets of
nucleotides—“codons”—and, since there are 20 amino acids, 21 things to encode. The
mapping between them is called the genetic code. The nuclear genome of virtually every
free-living organism uses exactly the same code (though there are a few exceptions). 55 This
is no great surprise, since any mutation causing a change to the code would necessarily
change the amino acid sequences encoded by huge numbers of genes; a few might not matter,
but there would inevitably be many for which the change was a lethal mutation.
Conversely, it is less amazing that animals’ mitochondria can be more flexible about
their code, since there are only 13 potential “victims.” Indeed, the mitochondrial genetic
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