The Vital Question: Why is life the way it is?

by Nick Lane

So we have a very peculiar situation, in which mitochondria apparently agitate for sex, as we’ve just seen, but the outcome is not that they spread from cell to cell but that half of them get digested. What’s going on here?

French Nobel laureate François Jacob once said that the dream of every cell is to become two cells. The surprise is not that they often do, but that they can be restrained for long enough to make a human being. For these reasons, mixing two populations of mitochondria in the same cell is just asking for trouble.

The more tissues there are in an adult, the greater the likelihood that a vital tissue will accumulate all the worst mitochondria. Conversely, with only one tissue type, this is not a problem, as there is no interdependence – no organs whose failure can undermine the function of the whole individual. In the case of a simple organism with a single tissue, then, increased variance is unequivocally good: it’s beneficial for the germline and not particularly detrimental to the body. We therefore predicted that the first animals, with (presumably) low mitochondrial mutation rates and very few tissues, should have had biparental inheritance and lacked a sequestered germline. But when early animals became slightly more complex, with more than a couple of different tissues, increased variance within the body itself becomes disastrous for adult fitness, as it inevitably produces both good and bad tissues – the heart attack scenario. To improve adult fitness, mitochondrial variance must be decreased so that nascent tissues all receive similar, mostly good, mitochondria.

If a mutation alters the identity of an amino acid in a protein, hydrogen bonds may be broken, or new ones formed. Whole webs of hydrogen bonds may shift a little, including those that pinion a redox centre into its correct position. It might well move by an ångström or so. The consequences of such tiny shifts are magnified by quantum tunnelling: an ångström this way or that could slow down electron transfer by an order of magnitude, or speed it by an equivalent factor. That’s one reason why mitochondrial mutations can be so catastrophic.

mitochondrial and nuclear genomes are diverging continuously.

Sex is needed to maintain the function of individual genes in large genomes, whereas two sexes help maintain the quality of mitochondria. The unforeseen consequence was that these two genomes evolve in totally different ways. Nuclear genes are recombined by sex every generation, whereas mitochondrial genes pass from mother to daughter in the egg cell, rarely if ever recombining. Even worse, mitochondrial genes evolve 10–50 times faster than genes in the nucleus, in terms of their rate of sequence change over generations, at least in animals. This means that proteins encoded by mitochondrial genes are morphing faster and in different ways compared with proteins encoded by genes in the nucleus; yet still they must interact with each other over distances of ångströms for electrons to transfer efficiently down the respiratory chain. It’s hard to imagine a more preposterous arrangement for a process so central to all living things – respiration, the vital force!

There are few better examples of the short-sightedness of evolution. This crazy solution was probably inevitable.

Thus we have three alterations to electron flux in respiration: first, electron transfer slows down, and so the rate of ATP synthesis also falls. Second, the highly reduced iron–sulphur clusters react with oxygen to produce a burst of free radicals, resulting in the release of cytochrome c from its tethering to the membrane. And third, if nothing is done to compensate for these changes, the membrane potential collapses (Figure 32). I have just described a curious set of circumstances first discovered in the mid 1990s and greeted at the time with ‘general stupefaction’. This is the trigger for programmed cell death, or apoptosis.

What came as a complete surprise was the central involvement of mitochondria, especially the bona fide respiratory protein cytochrome c. Why on earth would the loss of cytochrome c from the mitochondria act as a signal for cell death?

Imagine a cross between a male and female from two closely related species, which produces viable offspring. But now look more carefully at these offspring: they are all male, or all female; or if both sexes are present, then one of the two sexes is sterile or otherwise maimed. Haldane’s rule says that this sex will be the male in mammals and the female in birds. The catalogue of examples that has been pieced together since 1922 is impressive: hundreds of cases conform to the rule, across many phyla, with surprisingly few exceptions for a subject as confounded by exceptions as biology.

These ideas, I must say, came as a revelation to me. The hypothesis that sex is determined ultimately by metabolic rate has been advanced over several decades

Selection is all about offspring. If organisms with large and irreplaceable brains leave more viable offspring than organisms with small replaceable brains, then they will thrive. Only when there is a distinction between the germline and soma can selection act in this way; but when it does, the body becomes disposable. Lifespan becomes finite. And cells that can’t meet their metabolic requirements will kill us in the end. That’s why the metabolic rate matters. Cells with a faster metabolic rate are more likely to fail to meet their demands, given the same mitochondrial output. Not only mitochondrial diseases, but also normal ageing and age-related diseases, are most likely to affect the tissues with the highest metabolic demands. And to come full circle – the sex with the highest metabolic demands. Males have a faster metabolic rate than females (in mammals at least). If there is some genetic defect in the mitochondria, that defect will be unmasked largely in the sex with the faster metabolic rate – the male. Some mitochondrial diseases are indeed more common in men than in women; Leber’s hereditary optic neuropathy, for example, is five times more prevalent in men, while Parkinson’s disease, which also has a strong mitochondrial component, is twice as common.

So there is a hypothetical death threshold (Figure 34). Above the threshold the cell, and by extension the whole organism, dies by apoptosis. Below the threshold the cell and the organism survive. This threshold is necessarily variable between different species. For bats and birds and other creatures with high aerobic requirements, the threshold must be set low – even a modest rate of free-radical leak from mildly dysfunctional mitochondria (with slight incompatibilities between mitochondrial and nuclear genomes) signals apoptosis and termination of the embryo. For rats and sloths and couch potatoes with low aerobic requirements, the threshold is set higher: a modest rate of free-radical leak is now tolerated, dysfunctional mitochondria are good enough, the embryo develops. There are costs and benefits to both sides. A low threshold gives a high aerobic fitness and a low risk of disease, but at the cost of a high rate of infertility and poor adaptability. A high threshold gives a low aerobic capacity and higher risk of disease but with the benefits of greater fertility and better adaptability. These are words to conjure with. Fertility. Adaptability. Aerobic fitness. Disease. We can’t cut much closer to the grain of natural selection than that. I reiterate: all these trade-offs emerge inexorably from the requirement for two genomes.

Apparently 40% of pregnancies end in what is known as ‘early occult miscarriage’. ‘Early’ in this context means very early – within the first weeks of pregnancy, and typically before the first overt signs of pregnancy.

If free radicals are bad, antioxidants are good. Antioxidants interfere with the noxious effects of free radicals, blocking the chain reactions, and so preventing the spread of damage.

‘By the 1990s it was clear that antioxidants are not a panacea for ageing and disease, and only fringe medicine still peddles this notion.’ The free-radical theory of ageing is one of those beautiful ideas killed by ugly facts. And boy, are the facts ugly. Not one tenet of the theory, as it was originally formulated, has withstood the scrutiny of experimental testing. There are no systematic measurements of an increase in free-radical leak from the mitochondria as we age. There is a small increase in the number of mitochondrial mutations, but with the exception of limited regions of tissue, they are typically found at surprisingly low levels, well below those known to cause mitochondrial diseases. Some tissues show evidence of accumulating damage, but nothing that resembles an error catastrophe, and the chain of causality is questionable.

Antioxidants most certainly do not prolong life or prevent disease. Quite the contrary. The idea has been so pervasive that hundreds of thousands of patients have enrolled in clinical trials over the past few decades. The findings are clear. Taking high-dose antioxidant supplements carries a modest but consistent risk. You are more likely to die early if you take antioxidant supplements.

I still think that a more subtle version of the free-radical theory is true? For several reasons. Two critical factors were missing from the original theory: signalling and apoptosis.

It seems most likely that free-radical signals optimise respiration, within individual mitochondria, by raising the number of respiratory complexes, so increasing respiratory capacity. Because mitochondria spend much of their time fusing together and then splitting apart again, making more complexes (and more copies of mitochondrial DNA) translates into making more mitochondria – what’s known as mitochondrial biogenesis.9 Free-radical leak can therefore increase the number of mitochondria, which between them make more ATP! Conversely, blocking free radicals with antioxidants prevents mitochondrial biogenesis, hence ATP synthesis falls as shown by Enriquez (Figure 35). Antioxidants can undermine energy availability.

Free radicals signal the problem that respiratory capacity is low, relative to demand. If the problem can be fixed by making more respiratory complexes, raising respiratory capacity, then all is well and good. If that does not fix the problem, the cell kills itself, removing its presumably defective DNA from the mix. If the damaged cell is replaced by a nice new cell (from a stem cell), then the problem has been fixed, or rather, eradicated.

Think about the problem here. The most incompatible mitochondria will tend to leak the most free radicals, and so make more copies of themselves. That can have one of two effects. Either the cell dies by apoptosis, removing its load of mitochondrial mutations, or it doesn’t. Let’s consider what happens if the cell dies first. Either it’s replaced, or it isn’t. If it is replaced, all is well. But if it’s not replaced, for example in brain or heart muscle, then the tissue will slowly lose mass.

lazy people don’t live longer – exercise is beneficial. So, within limits, is calorie restriction and low-carbohydrate diet. All promote a physiological stress response (as do pro-oxidants) which tends to clear out defective cells and bad mitochondria, promoting survival in the short term, but typically at the cost of lowering fertility.

I doubt we will ever find a way of living much beyond 120 by merely fine-tuning our physiology.

There is a straightforward prediction here: selection for greater aerobic capacity, over generations, should prolong lifespan.