Why Mitochondria Make Complexity Possible

In the last chapter, we considered why bacteria have remained small and unsophisticated, at least in terms of their morphology. The reasons relate mostly to the selection pressures that face bacteria. These are different from eukaryotic cells because bacteria, for the most part, do not eat each other. Their success in a population therefore depends largely on the speed of their replication. This in turn depends on two critical factors: first, copying the bacterial genome is the slowest step of replication, so the larger the genome, the slower is replication; and second, cell division costs energy, so the least energetically efficient bacteria replicate the slowest. Bacteria with large genomes will always tend to lose out in a race against those with smaller genomes, because bacteria swap genes, by way of lateral gene transfer, and so can keep loading up cassettes of useful genes, and throwing them away again as soon as they become burdensome. Bacteria are therefore faster and more competitive if genetically unburdened.

If two cells have the same number of genes, and have equally efficient energy-generating systems, then the cell that can replicate the fastest will be the smaller of the two. This is because bacteria depend on their outer cell membrane to generate energy, as well as absorbing food. As bacteria become larger in size, their surface area rises more slowly than their internal volume, so their energetic efficiency tails away. Larger bacteria are energetically less efficient, and always likely to lose out in competition with smaller bacteria. Such an energetic penalty against large size precludes phagocytosis, for physically engulfing prey demands both large size and plenty of energy to change shape. Eukaryotic-style predation—catching and physically eating prey—is therefore absent among bacteria. It seems that eukaryotes escape this problem because they generate their energy internally, which makes them relatively independent of their surface area, and enables them to become many thousands of times larger without losing energetic efficiency.

As a distinction between the bacteria and eukaryotes, this reason sounds flimsy. Some bacteria have quite complex internal membrane systems and could be released from the surface-area constraint, yet still don't approach eukaryotes in size and complexity. Why not? We'll look into a possible answer in this chapter, and it is this: mitochondria need genes to control respiration over a large area of internal membranes. All known mitochondria have retained a contingent of their own genes. The genes that mitochondria retain are specific, and the mitochondria were able to retain them because of the nature of their symbiotic relationship with their host cell. Bacteria do not have this advantage. Their tendency to throw away any superfluous genes has prevented them from ever harnessing the correct core contingent of genes to govern energy generation, and this has always prevented them from developing the size and complexity of the eukaryotes.

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 mito-chondrial 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.

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