Power, Sex, Suicide: Mitochondria and the Meaning of Life (40 page)

The second possibility is that the mitochondria really did inherit the
bcl-2
proteins from their bacterial ancestors, as suggested by Frade and Michaelidis, and discussed in the previous chapter. This can only be proved by similarities in the gene sequences, which have not been found so far. What’s more, such similarities would need to be found among representatives of the α-proteo-bacteria, the known ancestors of the mitochondria, or else lateral gene transfer at a later stage could not be ruled out. Clearly, if lateral gene transfers took place later on, that would say nothing about the initial relationship between the mitochondria and the host cells. So a more systematic sampling of genes across the α-proteobacteria might lend support to this hypothesis, but in the meantime the structural similarities are suggestive at best.

Finally, it’s feasible that
N. gonorrhoea
and other parasitic bacteria acquired their porins from the mitochondria, rather than the other way around. Such transfers of genes from host to parasite are common. If this were the case, we might expect to find similarities in the gene sequences between the mitochondria and the parasites. The lack of such genetic similarities might only be for want of trying—they’ll turn up when we have sequenced more genes—or it might be that sequence similarities have simply been lost over time, smothering any evidence of common ancestry. This is not unlikely, as the unceasing evolutionary war waged between parasite and host means that parasite genes are notoriously volatile. Furthermore, the bacterial porins do not themselves bring about the whole of apoptosis—they merely plug into the host’s existing death apparatus. Effectively, they bring with them a portable ‘on’ switch, which
triggers the host’s own machinery. The behaviour of parasites that cause cell death today is therefore not comparable with the inferred role of the protomitochondria, for they would have had to bring the entire death apparatus with them, and implement it in the host cell without killing themselves in the process. (Today, of course, the mitochondria die along with their host cell.)

On the basis of evidence to date, it isn’t possible to resolve between these three possibilities. Nonetheless, the picture of parasite wars painted by Frade and Michaelidis does seem at least coherent and plausible. Or does it? There are a few other, rather knotty, problems with the story. First and foremost, mitochondria are no longer independently replicating cells, and in all probability they would have lost their independence soon after their genes began to be transferred to the host cell nucleus. Once a few critical genes were held hostage in the nucleus, then the mitochondria could gain nothing from killing their host, as they could no longer survive independently out in the wild. Their future was tied to that of their host. That’s not to say they could gain nothing from
manipulating
their host, but surely they could not gain from actually killing it. In contrast, none of the parasites that we’ve discussed, even tiny
Rickettsia
, has ever lost its independence. They all maintain complete control over their life cycle and resources. They can get away with murder in a way that mitochondria cannot.

Exactly when mitochondria lost power over their own future is unknown, but it is likely to have happened quite early in the evolution of the eukaryotic cell. Consider, for example, the evolution of the ATP carrier, the membrane pump that exports ATP from the mitochondria (see
page 145
). For the first time, this enabled eukaryotic cells to extract energy in the form of ATP from mitochondria (which could hardly even be called mitochondria until then). It was a symbolic moment, for the symbionts no longer had control of their own energy resources—they had suffered a loss of sovereignty. For the mitochondria, it marked the transition from a symbiotic relationship to a captive state. We can date the transition reasonably accurately by comparing the sequences of the ATP-carrier gene in the various different groups of eukaryotes. In particular, the fact that the carrier is found in all groups of eukaryotes, including plants, animals, fungi, algae, and protozoa, implies that it evolved before the divergence of these groups, placing it very early in the history of the eukaryotic cell. I need hardly say that this places it well before the evolution of multicellular organisms; from fossil evidence, probably by a few hundred million years.

So we have a gap. It seems very likely that the mitochondria lost their autonomy well before the evolution of true multicellular organisms. During this period, the mitochondria could gain nothing from killing their hosts, for they could not survive independently. Nor could their hosts gain anything from being killed, for they were not yet part of a multicellular organism. Thus the
current advantages of apoptosis, the ruthless maintenance of a police state in multicellular organisms, could not apply.

This is a paradox. The persistence of a dedicated machinery of death must have been actively detrimental to both host and mitochondria. We might expect it to have been jettisoned by natural selection, yet we know that it was maintained. We also know that much of the death apparatus was inherited from the mitochondria, rather than from the host (or evolving more recently). And to cap it all, I have argued in favour of the hydrogen hypothesis, which contends that the eukaryotic cell originated in a metabolic union between two peacefully cohabiting cells, neither of which could gain from killing the other. I seem to have argued us into a blind alley, to wit: a collaborative cell brought with it to a peaceful union a fully developed death apparatus, detrimental to both parties, which persisted against all the odds for a few hundred million years before it happened to find a use. Can this crazy scenario be rationalized? Yes, but only if we are prepared to make a concession—the death apparatus did not always cause death. Once upon a time, it caused sex.

Let’s consider the first eukaryotes from the point of view of the peaceful cohabitation proposed by the hydrogen hypothesis. In the introduction to
Part 5
, we discussed the different levels at which natural selection operates—the level of the individual as a whole, or its constituent cells, or the mitochondria within the cells, or of course the genes themselves. We saw that it is not necessarily helpful, when considering cells that replicate asexually like bacteria, to think about natural selection operating at the level of the genes. Instead, selection works mostly at the level of the individual cells, which in this case are the true replicating units. This background will now prove invaluable to us, for we must consider the interests of the mitochondria and their host cells separately, in the early days of the eukaryotic merger. In those days, both the mitochondria and the host cells could be thought of as separate cells (and we shall see in the next few chapters that in many ways it still helps to consider them in this way).

So what were the private interests of the proto-mitochondria and their host cells? Given their combination of autonomy and uneasy mutual dependency, how could they have acted out their own interests? A compelling answer was put forward in 1999, by one of the most fertile thinkers in evolutionary biochemistry, Neil Blackstone, at Northern Illinois University, along with Douglas Green, one of the pioneers of cytochrome c release in apoptosis, at UCSD, La Jolla.

Like all cells, it is in the interest of mitochondria to proliferate. As soon as their own future has been tied to that of their host, they can gain nothing from killing this host and moving on to another—they could not survive the interim
in the wild. There’s also a limit to how far the mitochondria can proliferate within a single host cell: a mitochondrial ‘cancer’ within the host would be detrimental to the cell as a whole, which would perish, along with all of its mitochondria. So the only way that the mitochondria can successfully proliferate is in line with the host cell. Each time the host cell divides, the mitochondrial population must double, to provide a contingent for each daughter cell. Of course, there’s nothing the host cell likes better than dividing either, so the interests of host and mitochondria are in common. If they were not, it is quite doubtful that the arrangement could have persisted as a stable relationship for two billion years. It would surely have torn itself asunder early on, and we would not have been here to be any the wiser.

But the interests of the mitochondria and the host cell are not always in common. What might happen if, for some reason, the host cell refused to divide? Clearly neither the host cell nor its mitochondria could then proliferate (well, the mitochondria
could
proliferate, but only to a certain point: it would be detrimental to the host, and so to the mitochondria themselves, if they continued proliferating until they produced a mitochondrial ‘cancer’ inside the cell). The consequences might differ depending on the reason the host cell refused to divide. The most likely reason is lack of food. In
Part 3
we noted that most bacteria spend most of their lives in stasis, despite their enormous capacity to replicate. The same must have applied to the early eukaryotes. If so, there was nothing to do but wait out the lean times, and resume proliferating again as soon as food became available. In this case, the interests of the mitochondria and the host cell are again in common: if the mitochondria pressed the host to divide without sufficient resources, both would perish. Better to devote the remaining resources to bolstering resistance to any physical stress likely to be encountered during the period of deprivation, such as heat, cold, and ultraviolet radiation. Under these conditions, many cells form a resistant spore, which survives the wait in a dormant state before springing back to life in times of plenty.

Another reason that might prevent the host cell from dividing is damage, in particular to the DNA of the cell nucleus. Now the interests of the host and the mitochondria begin to diverge. Let’s assume that food is plentiful, but the host cell is nonetheless unable to divide. You can almost picture the trapped mitochondria, faces pressed against the bars, yelling ‘Let me out! Unfairly imprisoned!’ In the meantime, their neighbouring cells grin and divide away, their mitochondria proliferating happily. What are the trapped mitochondria to do? They don’t gain anything from killing their host, as they’d soon be dead themselves. But they
would
gain if the host cell
fused
with another, and recombined its DNA with that of the partner. Recombination of DNA is common in bacteria, and is the very basis of sex in eukaryotes. The fused cell gains a new lease of life—and the mitochondria a new playground.

Why
sex evolved in eukaryotes is still fiercely contested, given its twofold cost (see
page 191
). It seems likely that several different factors contribute. Sex tends to mask damaged DNA, as the damaged gene is likely to be paired with an undamaged copy of the same gene; and the variety generated by recombination probably gives cells a competitive edge over parasites—a theory championed by Bill Hamilton. Recent data imply that neither reason alone is sufficiently strong in all circumstances to account for the evolution of sex; but they don’t conflict with each other, and it seems likely that the benefits of sex are many pronged. On the other hand, its origin is a mystery. Bacteria recombine genes, but never
fuse
cells. In contrast, sexual reproduction in most eukaryotes involves the fusion of two cells, then the fusion of their nuclei, and finally the recombination of their genes, an altogether more committing act. What made eukaryotic cells fuse in the first place? Losing the unwieldy cell wall of bacteria no doubt made the physical act of fusion far more practicable, but this still does not account for the actual
urge
to fuse. Cells don’t fuse all the time, so there is nothing about the wall-less state in itself that promotes fusion. Might it be that early eukaryotic cells were manipulated by their mitochondria to fuse together? If so, could mitochondrial sabotage explain the origin of sexual fusion? Tom Cavalier-Smith, whom we met in
Part 1
, has reasoned that cell fusion would have been common in the early eukaryotes: he argues that the form of cell division in sex (meiosis), in which the chromosomal number is first doubled, and then halved, evolved via a few simple steps, as a means of restoring the original number of genes and nuclei after cellular fusions. In this case, mitochondria might have agitated for a fusion that was likely to happen in due course anyway.

The question of whether the mitochondria can manipulate the host cell is a serious one. We know they do today: they cause apoptosis. But might they have done so in the early days of the eukaryotic cell too? Neil Blackstone has suggested an ingenious way in which they could have done, and it explains both the urge to fuse and ultimately the evolution of apoptosis.

Think about the respiratory chain. We discussed the leakage of free radicals from the chain in
Part 3
. Paradoxically, the rate of free-radical leakage does not correspond to the rate of respiration, as one might think intuitively, but rather depends on the availability of electrons (ultimately derived from food) and oxygen. Because these factors vary continuously, free-radical production shifts according to circumstances. Sudden bursts of free-radical production can affect the behaviour of the cell.

If a cell is growing and dividing quickly, and so has a high demand for
fuel (and plenty to meet this demand), there is a fast flux of electrons down the respiratory chain to oxygen. In these circumstances, relatively few free radicals leak from the chain. This is because they are more likely to pass down the line of least resistance, from one electron acceptor to the next in the chain, and finally to oxygen. Blackstone describes the chain in these circumstances as a well-insulated wire, through which electricity flows as a current of electrons. So, fast growth with plentiful fuel equates to a low leakage of free radicals.

What about times of starvation? Now there is little fuel, and practically no electrons passing down the respiratory chain. There may be plenty of oxygen around, but no spare electrons to stray off and form free radicals. If we think of the respiratory chains as little electrical wires, then starvation equates to a grid power failure: it’s impossible to suffer an electric shock if the mains supply is dead. Free-radical leakage is low because there is no electron flow at all.