The Mitochondrial Free Radical Theory of Aging - Supernova: Pliki

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The Mitochondrial Free Radical Theory of Aging
same machinery is used for all proteins, so one would think it could easily have been extended
to handle those last 13.
Moreover, apart from one very recent report 3 there is no evidence that any genes have
ever moved the other way. There is evidently a selective advantage associated with having
one’s genes in the nucleus, albeit not enough of one to have pushed the transfer process to
completion. We do not know what this advantage is, but it could be as simple as that such
genes then benefit from Mendelian inheritance, which seems to be evolutionarily desirable
since it allows the gene to escape from “Muller’s ratchet.” 4,5
There are probably two main reasons why we retain these 13. The first one goes some
way towards explaining why it is precisely those 13, rather than some others. They are all
subunits of the OXPHOS enzymes, which means they all exist embedded in the inner
mitochondrial membrane. Transmembrane proteins have an amino acid composition that
tends to push them into solution in lipids (such as membranes) and out of solution in
water. This is called, for obvious reasons, hydrophobicity, and it can be quantitatively
calculated from the amino acid sequence as a property of the whole protein or of a region of
it. It turns out that almost all the 13 mt-coded proteins have several regions of high
hydrophobicity, whereas imported proteins have fewer (though some have many regions
with moderate hydrophobicity). 6 So, one reason why these 13 genes are still encoded by the
mtDNA may well be because the protein import machinery is not good enough at handling
proteins which have this sort of sequence.
The second reason requires some introduction. It seems that all but these 13 were
transferred to the nucleus a very long time ago. Phylogenetic analysis tells us that all but one
of them moved before the animal kingdom diverged from fungi, and that last one—ATPase
subunit 9—must have moved quite soon after that, because it is in the nucleus of all animals
that have been studied, though it is still in the mitochondrion in most fungi. 7 The only
difference that has been found so far in the complement of genes in different animals’ mtDNA
is that nematodes and some mussels may have transferred one more gene, ATPase 8, to the
nucleus. 8,9 (I say “may” because all we know at present is that ATPase 8 is not encoded in
these species’ mtDNA: it has not yet been found in the nuclear genome either, so it may not
be retained at all.) It thus seems that evolution was getting along reasonably well in
transferring genes, and that then suddenly everything froze.
An explanation can be seen by comparing animals with plants. In plants, the transfer
process seems not to have frozen quite so solid. For example, the gene for cytochrome c
oxidase subunit 2 is in the mitochondria of almost all plants (and all animals) but is in the
nucleus of some legumes such as Vigna radiata. 10 Since legumes form a relatively small
taxon in the plant kingdom, this transfer must have happened fairly recently. A similarly
recent transfer of cytochrome c oxidase subunit 3 has been identified in the club moss
Selaginella elegans. 11
The basis for this difference is not known for sure, but it is very likely to be because the
mtDNA of animals uses a slightly abnormal genetic code. Almost all eukaryotes use exactly
the same genetic code in their nuclei; so do almost all bacteria, and it is virtually certain that
at the time of the original endosymbiotic event the primordial mitochondrion also used
that code. Since so many genes would be affected by any change in the code, there is a huge
selective pressure to eliminate any mutation causing such a change in a cytoplasmic tRNA.
But mitochondria have their own tRNAs, which are the molecules in which the genetic code
is defined. As the number of protein-coding genes in the mtDNA steadily diminished, the
pressure against drift in the code correspondingly became less and less. Eventually, some
time after the divergence of plants from animals (but probably before the divergence of
animals from fungi) there was a switch in just one codon. This switch thus affected fungi
and animals but not plants. The trinucleotide UGA, which in the standard code means
“stop,” changed so that in mitochondria it meant “tryptophan.”