Power, Sex, Suicide: Mitochondria and the Meaning of Life (48 page)

Secondly, the dual-control hypothesis gives a positive basis for natural selection. One difficulty with the selfish-conflict theory is that selection can only act to eliminate the negative consequences of genome conflict. However, we’ve seen that heteroplasmy exists in many circumstances without obvious competition between the two genomes—for example in angiosperms, some fungi, and bats. If the detrimental effects of genomic competition are limited, then why does natural selection
generally
favour uniparental inheritance? It would do so if uniparental inheritance were positively beneficial most of the time, rather than merely mildly detrimental part of the time. The dual-control theory gives a good reason why this would be the case: the fittest individuals generally inherit the mitochondrial DNA only from the mother, as this enables the best match of nuclear and mitochondrial genomes. And if the fittest offspring tend to inherit their mitochondrial genes from only one of two parents, we have satisfied the condition for two sexes: the female sex supplies the mitochondria, the male sex generally does not.

So where and how does selection act to ensure harmony between nuclear and mitochondrial genes? The probable answer is during the development of the female embryo, when the overwhelming majority of egg cells, or oocytes, die by apoptosis. The fittest cells apparently pass through a bottleneck, which selects for mitochondrial function. While little is known about how such a bottleneck works—and some dispute its very existence—the broad outlines conform wholly to the expectations of the dual control hypothesis. It seems that oocytes are selected on the basis of how well their mitochondria function against the nuclear background.

The fertilized egg cell (the zygote) contains about 100 000 mitochondria, 99.99 per cent of which come from the mother. During the first two weeks of embryonic development, the zygote divides a number of times to form the embryo. Each time the mitochondria are partitioned among the daughter cells, but they don’t actively divide themselves: they remain quiescent. So for the first two weeks of pregnancy, the developing embryo has to make do with the 100 000 mitochondria it inherited from the zygote. By the time the mitochondria finally begin to divide, most cells are down to a couple of hundred each. If their function is not sufficient to support development, the embryo dies. The proportion of early miscarriages caused by energetic failures is unknown, but energetic insufficiency certainly causes many failures of chromosomes to separate properly during cell division, giving rise to anomalies in the number of chromosomes such as trisomy
(three, rather than two, copies of a chromosome). Virtually all of these anomalies are incompatible with full-term development; indeed only Trisomy 21 (three copies of chromosome 21) is mild enough to deliver a live birth; and even so, babies born with this anomaly have Down syndrome.

In a female embryo, the earliest recognizable egg cells (the primordial oocytes) first appear after two to three weeks of development. Exactly how many mitochondria these cells contain is controversial, and estimates range from less than 10 to more than 200. The most authoritative survey, by Australian fertility expert Robert Jansen, is at the low end of this range. Either way, this is the start of the mitochondrial bottleneck, through which selection for the best mitochondria takes place. If we persist in clinging to the idea that all the mitochondria inherited from our mother are exactly the same, then this step might seem inexplicable, but in fact there is a surprising variety of mitochondrial sequences in different oocytes taken from the same ovary. One study by Jason Barritt and his colleagues at the St Barnabus Medical Center in New Jersey, showed that more than half the immature oocytes of a normal woman contain alterations in their mitochondrial DNA. This variation is mostly inherited, and so must also have been present in the immature ovaries of the developing female embryo. What’s more, this degree of variation is what remains
after
selection, so presumably the mitochondrial sequences are even more variable in the developing female embryo, where the selection takes place.

How does this selection work? The bottleneck means that there are only a few mitochondria in each cell, making it more likely that all of them will share the same mitochondrial gene sequence. Not only are there few mitochondria, but each mitochondrion has only one copy of its chromosome, rather than the usual five or six. Such restriction precludes compensation for poor function: any mitochondrial deficits are effectively paraded naked, and their inadequacies can be magnified to the point that they are detected and eliminated. The next stage is amplification—rushing out of the constraints of the bottleneck. Having established a direct match between a single clone of mitochondria and the nuclear genes, it is necessary to test how well they work together. To do so, the cells and their mitochondria must divide, and this relies on both mitochondrial and nuclear genes. The behaviour of the mitochondria is striking when examined down the electron microscope—they encircle the nucleus like a bead necklace. This remarkable configuration surely betokens some kind of dialogue between the mitochondria and the nucleus, but at present we know next to nothing about how it may work.

The replication of oocytes in the embryo over the first half of pregnancy takes their number from around 100 after 3 weeks, to 7 million after 5 months (a rise of about 2
¹⁸
). The number of mitochondria climbs to some 10 000 per cell, or a total of about 35 billion in all the germ cells combined (a rise of 2
²⁹
), a massive
amplification of the mitochondrial genome. Then follows some kind of selection. How this selection works is quite unknown, but by the time of birth the number of oocytes has fallen from 7 million to about 2 million, an extraordinary wastage of 5 million oocytes, or nearly three quarters of the total. The rate of loss abates after birth, but by the onset of menstruation there are only about 300 000 oocytes left; and by the age of 40, when there is a steep decline in oocyte fertility, just 25 000. After that, decline is exponential into menopause. Of the millions of oocytes in the embryo, only about 200 ovulate during a woman’s entire reproductive life. It’s hard not to believe that some form of competition is going on—that only the best cells win out to become mature oocytes.

There are indeed suggestions of purifying selection at work. I mentioned that half of all immature oocytes in the ovaries of a normal woman have errors in their mitochondrial sequence. Only a tiny fraction of these immature eggs mature, and only a few mature eggs are successfully fertilized to create an embryo. What selects for the best eggs is unknown, but the proportion of mitochondrial errors is known to fall to about 25 per cent in early embryos. Half of the mitochondrial error has been eliminated, implying that some kind of selection has taken place. Of course, most embryos also fail to mature (the great majority die in the first few weeks of pregnancy), and again the reasons are unknown. Nonetheless, it is known that the incidence of mitochondrial mutations in newborn babies is a tiny fraction of that in early embryos, implying that a purge of mitochondrial errors really has taken place. There is other indirect evidence of mitochondrial selection. For example, if the selection of oocytes acts as a proxy for natural selection in adults, avoiding all the costly investment to produce an adult, then species that invest their resources most heavily in a small number of offspring might be expected to have the best ‘filter’ for quality oocytes—they have the most to lose from getting it wrong. This does actually seem to be the case. The species that have the smallest litters also have the tightest mitochondrial bottleneck (the smallest number of mitochondria per immature oocyte), and the greatest cull of oocytes during development.

Although we don’t know how such selection acts, it is plain that failing oocytes die by apoptosis, and the mechanism certainly involves the mitochondria. It is possible to preserve an oocyte otherwise destined to die simply by injecting a few more mitochondria—this is the basis of ooplasmic transfer, the technique we mentioned on
page 240
. The fact that such a crude manoeuvre actually does protect against apoptosis suggests that the fate of the oocyte really does depend on energy availability; and indeed there is a general correlation between ATP levels and the potential for full-term development. If energy levels are insufficient, cytochrome c is released from the mitochondria, and the oocyte commits apoptosis.

All in all, there are many tantalizing hints that selection is taking place in oocytes for the dual control system of mitochondrial and nuclear genes, although there is as yet little direct evidence. This, truly, is twenty-first-century science. But if it is shown that oocytes are the testing ground for mitochondrial performance against the nuclear genes then this would be good evidence that two sexes exist to ensure a perfect match between the nucleus and the mitochondria. Having now selected an oocyte on the basis of its mitochondrial performance, the last thing we need is this special relationship to be messed up by a big injection of sperm mitochondria adapted to a different nuclear background.
¹

We have much to learn about the relationship between the mitochondrial and nuclear genes in oocytes, but we know rather more about this relationship in other, older cells. In ageing cells, mitochondrial genes accumulate new mutations and the dual genomic control begins to break down. Respiratory function declines, free-radical leakage rises, and the mitochondria begin to promote apoptosis. These microscopic changes are writ large as we age. Our energy diminishes, we become far more vulnerable to all kinds of diseases, and our organs shrink and wither. In
Part 7
, we’ll see that the mitochondria are central not only to the beginning of our lives, but also to their end.

Why Mitochondria Kill us in the End

Animals with a fast metabolic rate tend to age quickly and succumb to degenerative diseases such as cancer. Birds are an exception because they combine a fast metabolic rate with a long lifespan, and a low risk of disease. They achieve this by leaking fewer free radicals from their mitochondria. But why does free-radical leakage affect our vulnerability to degenerative diseases that on the face of it have little to do with mitochondria? A dynamic new picture is emerging, in which signalling between damaged mitochondria and the nucleus plays a pivotal role in the cell’s fate, and our own.

Ageing and death—mitochondria divide or die, depending on their interactions with the nucleus

The immortal elves in Tolkein’s immortal epic are as mortal as the next man. They die in droves on the battlefield. What they
don’t
do is age, or at least not much. Elrond, Lord of Rivendell in
The Lord of the Rings
, was thousands of years old, dwarfing even biblical lifespans. Tolkein described his face as ‘ageless, neither old nor young, though in it was written the memory of many things, both glad and sorrowful. His hair was dark as the shadows of twilight…’

Is this just the whimsy of an imaginative mind? Not necessarily. While ageing and the degenerative diseases it carries with it are the bane of the western world, they are not a universal currency throughout nature. Many giant trees, for example, live for thousands of years. Admittedly, trees are a long way removed from ourselves, and in any case much of the tree is just dead structural support. Better examples, far closer to home, are many birds. Parrots can live for over a hundred years, the albatross for more than a hundred and fifty. Many gulls live for seven or eight decades and show few overt signs of ageing in a way that we can recognize. A famous pair of photographs depicts the Scottish zoologist George Dunnet with a fulmar petrel that he had captured and ringed in Orkney. The first photograph shows Professor Dunnet as a handsome young man with a handsome young bird in 1952. The second was taken in 1982, and shows Dunnet with the same ringed fulmar, which he fortuitously recaptured thirty years later, again in Orkney. Dunnet is by now betraying the ravages of age, but the bird has aged not a jot, at least to the naked eye. A third photograph, which I have never managed to see, apparently pictures Dunnet with the same fulmar in 1992, just a couple of years before the death, after protracted illness, of one of them. Rest in peace, Professor Dunnet.