Power, Sex, Suicide: Mitochondria and the Meaning of Life (25 page)

To understand the reasons why mitochondrial genes are important, and why bacteria can’t acquire the correct set of genes for themselves, we’ll need to penetrate further into the intimate relationship between the cells that took part in the original eukaryotic union, two billion years ago. We’ll take up the story where we left off in
Part 1
. There, we parked the chimeric eukaryote as a cell that had mitochondria but had not yet developed a nucleus. Because a eukaryotic cell is, by definition, a cell that has a ‘true’ nucleus, we can’t really refer to our chimera as a eukaryote. So let’s think now about the selection pressures that turned our strange chimeric cell into a proper eukaryotic cell. These pressures hold the key not just to the origin of the eukaryotic cell, but also to the origin of real complexity, for they explain why bacteria have always remained bacteria: why they could never evolve into complex eukaryotes by natural selection alone, but required symbiosis.

Recall from
Part 1
that the key to the hydrogen hypothesis is the transfer of genes from the symbiont to the host cell. No evolutionary novelties were called for, beyond those that already existed in the two collaborating cells entered in an intimate partnership. We know that genes were transferred from the mitochondria to the nucleus, because today mitochondria have few remaining genes, and there are many genes in the nucleus that undoubtedly have a mitochondrial origin, for they can be found in the mitochondria of other species that lost a different selection of genes. In all species, mitochondria lost the overwhelming majority of their genes—probably several thousand. Exactly how many of these genes made it to the nucleus, and how many were just lost, is a moot point among researchers, but it seems likely that many hundreds did make it to the nucleus.

For those not familiar with the ‘stickiness’ and resilience of DNA, it may seem akin to a conjuring trick for genes from the mitochondria to suddenly appear in the nucleus, like a rabbit produced from a top hat. How on earth did they do that? In fact such gene hopping is commonplace among bacteria. We have already noted that lateral gene transfer is widespread, and that bacteria routinely take up genes from their environment. Although we normally think of
the ‘environment’ as outside the cell, acquiring spare genes from inside the cell is even easier.

Let’s assume that the first mitochondria were able to divide within their host cell. Today, we have tens or hundreds of mitochondria in a single cell, and even after two billion years of adaptation to living within another cell they still divide more or less independently. At the beginning, then, it’s not hard to picture the host cell as having two or more mitochondria. Now imagine that one dies, perhaps because it can’t get access to enough food. As it dies, it releases its genes into the cytoplasm of the host cell. Some of these genes will be lost altogether, but a handful might be incorporated into the nucleus, by means of normal gene transfer. This process could, in principle, be repeated every time a mitochondrion dies, each time potentially transferring a few more genes to the host cell.

Such transfer of genes might sound a little tenuous or theoretical, but it is not. Just how rapid and continuous the process can be in evolutionary terms was demonstrated by Jeremy Timmis and his colleagues at the University of Adelaide in Australia, in a
Nature
paper of 2003. The researchers were interested in chloroplasts (the plant organelles responsible for photosynthesis), rather than mitochondria, but in many respects chloroplasts and mitochondria are similar: both are semi-autonomous energy-producing organelles, which were once free-living bacteria, and both have retained their own genome, albeit dwindling in size. Timmis and colleagues found that chloroplast genes are transferred to the nucleus at a rate of about 1 transfer in every 16 000 seeds in the tobacco plant
Nicotiana tabacum
. This may not sound impressive, but a single tobacco plant produces as many as a million seeds in a single year, which adds up to more than 60 seeds in which at least one chloroplast gene has been transferred to the nucleus—in every plant, in every generation.

Very similar transfers take place from the mitochondria to the nucleus. The reality of such gene transfers in nature is attested by the discovery of duplications of chloroplast and mitochondrial genes in the nuclear genomes of many species—in other words the same gene is found in both the mitochondria or chloroplast
and
in the nucleus. The human genome project has revealed that there have been at least 354 separate, independent transfers of mitochondrial DNA to the nucleus in humans. These DNA sequences are called
numts
, or nuclear-mitochondrial sequences. They represent the entire mitochondrial genome, in bits and pieces: some bits repeatedly, others not. In primates and other mammals, such numts have been transferred regularly over the last 58 million years, and presumably the process goes back further, as far as we care to look. Because DNA in mitochondria evolves faster than DNA in the nucleus, the sequence of letters in numts can act as a time capsule, giving an impression of what mitochondrial DNA might have looked like in the distant past. Such alien
sequences can cause serious confusion, however, and were once mistaken for dinosaur DNA, leaving one team of researchers with red faces.

Gene transfer continues today, occasionally making itself noticed. For example, in 2003, Clesson Turner, then at the Walter Reed Army Medical Center in Washington, and collaborators, showed that a spontaneous transfer of mitochondrial DNA to the nucleus was responsible for causing the rare genetic disease Pallister-Hall syndrome in one unfortunate patient. How common such genetic transfers are in the pantheon of inherited disease is unknown.

Gene transfers occur predominantly in one direction. Think back again to the first chimeric eukaryote. If the host cell were to die, it would release its symbionts, the proto-mitochondria, back into the environment, where they may or may not perish—but regardless of their fate, the experiment in chimeric co-existence would certainly have perished. On the other hand, if a single mitochondrion were to die, but a second viable mitochondrion survived in the host cell, then the chimera as a whole would still be viable. To get back to square one, the surviving mitochondrion would just have to divide. Each time a mitochondrion died, the genes released into the host cell could potentially be integrated into its chromosome by normal genetic recombination. This means there is a gene ratchet, favouring the transfer of genes from the mitochondria to the host cell, but not the other way around.

What happens to the genes that are transferred? According to Bill Martin, whom we met in both
Parts 1
and
2
, such a process might account for the origin of the eukaryotic nucleus. To understand how, we need to recall two points that we have discussed in earlier chapters. First, recall that Martin’s hydrogen hypothesis argues that the eukaryotic cell was first forged from the union of an archaeon and a bacterium. And second, recall from
Chapter 6
(
page 98
) that archaea and bacteria have different types of lipid in their cell membranes. The details don’t matter here, but consider the kind of membranes we would expect to find in that first, chimeric eukaryote. The host cell, being an archaeon, should have had archaeal membranes. The mitochondria, being bacterial, should have had bacterial membranes. So what do we actually see today? Eukaryotic membranes are uniformly bacterial in nature—both in their lipid structure and in many details of their embedded proteins (like the proteins that make up the respiratory chain, and similar proteins found in the nuclear membrane). The bacterial-style membranes of the eukaryotes include the cell membrane, the mitochondrial membranes, other internal membrane structures, and the double nuclear membrane. In fact there is no trace of the original archaeal membranes in the eukaryotes, despite the fact that other
features make it virtually certain that the original host cell was indeed an archaeon.

Such basic consistency, when we would expect to find disparity, has led some researchers to question the hydrogen hypothesis, but Martin considers the apparent anomaly to be a strength. He suggests that the genes for making bacterial lipids were transferred to the host cell, along with many other genes. Presumably, if functional, the genes went ahead with their normal tasks, such as making lipids; there is no reason why they should not function normally as before. But there may have been one difference—the host cell may have lost the ability to target protein products to particular locations in the cell (protein targeting relies on an ‘address’ sequence that differs in different species). The host cell may therefore have been able to
make
bacterial products, such as lipids, but not known exactly what to do with them; in particular, where to send them. Lipids, of course, don’t dissolve in water, and so if not targeted to an existing membrane would simply precipitate as lipid vesicles—spherical droplets enclosing a hollow watery space. Such droplets fuse as easily as soap bubbles, extending into vacuoles, tubes, or flattened vesicles. In the first eukaryote, these vesicles might simply have coalesced where they were formed, around the chromosome, to form loose, baggy membrane structures. Now this is exactly the structure of the nuclear membrane today—it is not a continuous double membrane structure like the mitochondria or chloroplasts, but is composed of a series of flattened vesicles, and these are continuous with the other membrane systems within the cell. What’s more, when modern eukaryotic cells divide, they dissolve the nuclear membrane, to separate the chromosomes destined for each of the daughter cells; and a fresh nuclear membrane forms around the chromosomes in each of these daughter cells. It does so by coalescing in a manner reminiscent of Martin’s proposal, and remains continuous with the other membrane systems of the cell. Thus, in Martin’s scenario, gene transfer accounts for the formation of the nuclear membrane, as well as all the other membrane systems of eukaryotic cells. All that was needed was a degree of orientational confusion, a map-reading hiatus.

There is still one step to go: we need to put together a cell with bacterial-style membranes throughout, in other words we need to replace the archaeal lipids of the cell membrane with bacterial lipids. How did this happen? Presumably, if bacterial lipids offered any advantage, such as fluidity, or adaptability to different environments, then any cell that expressed only the bacterial lipids would be at an advantage. Natural selection would ensure that the archaeal lipids were replaced, if such an advantage existed: there was little call for evolutionary ‘novelty’; it was merely a matter of playing with existing parts. It remains possible, however, that some eukaryotes did not go the whole hog. It would be interesting to know if there are still any primitive eukaryotic cells that retain
vestiges of archaeal lipids in their membranes. In support of the possibility, virtually all eukaryotes, including fungi, plants, and animals like ourselves still possess all the genes for making the basic carbon building blocks of archaeal lipids, the
isoprenes
(see
page 99
). We don’t use them for building membranes any more, however, but for making an army of
isoprenoids
, otherwise known as terpenoids or terpenes. These include any structure composed of linked isoprene units, and together make up the single largest family of natural products known, totalling more than 23 000 catalogued structures. These include steroids, vitamins, hormones, fragrances, pigments, and some polymers. Many isoprenoids have potent biological effects, and are being used in pharmaceutical development; the anticancer drug
Taxol
, for example, a plant metabolite, is an isoprenoid. So we haven’t lost the machinery for making archaeal lipids at all; if anything, we have enriched it.

If his theory is correct, then Martin has derived an essentially complete eukaryotic cell via a simple succession of steps: it has a nucleus enveloped by a discontinuous double membrane; it has internal membrane structures; and it has organelles such as mitochondria. The cell is free to lose its cell wall (but not, of course, its external cell membrane), as it no longer needs a periplasm to generate energy. Being derived from a methanogen, it wraps its genes in histone proteins and has a basically eukaryotic system of transcribing its genes and building proteins (see
Part 1
). On the other hand, this hypothetical progenitor eukaryotic cell probably did not engulf its food whole by phagocytosis—despite having a cytoskeleton (inherited from the archaea or the bacteria), it has not yet derived the dynamic cytoskeleton characteristic of mobile protozoa like amoeba. Rather, the first eukaryotes may have resembled unicellular fungi, which secrete various digestive enzymes into their surroundings, to break down food externally. This conclusion is corroborated by some recent genetic studies, but we won’t look into these here, for too many uncertainties remain.

So the transfer of genes from the mitochondria to the host cell is capable of explaining the origin of the eukaryotic cell, without requiring any evolutionary innovations (new genes with different functions) whatsoever. Yet the sheer
ease
of gene transfer raises another suspicious question. Why are there any genes left in the mitochondria at all? Why were they not all transferred to the nucleus?

There are big disadvantages to retaining genes in the mitochondria. First, there are hundreds, even thousands of copies of the mitochondrial genome in each cell (usually 5 to 10 copies in every mitochondrion). This enormous copy-number is one of the reasons that mitochondrial DNA is so important in
forensics, and in identifying ancient remains—from such an embarrassment of riches, it is usually possible to isolate at least a few mitochondrial genes. But by the same token, it also means that whenever the cell divides a vast number of ostensibly superfluous genes must be copied. Not only that, but every single mitochondrion is obliged to maintain its own genetic apparatus, enabling it to transcribe its genes and build its own proteins. By thrifty bacterial standards (which, as we have seen, eliminate any unnecessary DNA post haste) the existence of these supernumerary genetic outposts seems a costly extravagance. Second, as we shall see in
Part 6
, there are potentially destructive consequences of competition between different genomes within the same cell—natural selection can pit mitochondria against each other, or against the host cell, with no consideration of the long-term cost, merely the short-term gain for the individual genes. Third, storing genes, vulnerable informational systems, in the immediate vicinity of the mitochondrial respiratory chains, which leak destructive free radicals, is equivalent to storing a valuable library in the wooden shack of a registered pyromaniac. The vulnerability of mitochondrial genes to damage is reflected in their high evolution rate—in mammals, some twentyfold greater than the nuclear genes.