Two people are dancing a waltz, and it is not going well. One is tall and the other short; one is graceful, the other flat-footed; and both are stepping to completely different rhythms. The result is chaos, and the dance falls apart. Their situation mirrors a problem faced by all complex life on Earth. Whether we’re animal or plant, fungus or alga, we all need two very different partners to dance in step with one another. A mismatch can be disastrous. Virtually all complex cells – better known as eukaryotes – have at least two separate genomes. The main one sits in the central nucleus. There’s also a smaller one in tiny bean-shaped structures called mitochondria, little batteries that provide the cell with energy. Both sets of genes must work together. Neither functions properly without the other. Mitochondria came from a free-living bacterium that was engulfed by a larger cell a few billion years ago. The two eventually became one. Their fateful partnership revolutionised life on this planet, giving it a surge of power that allowed it to become complex and big (see here for the full story). But the alliance between mitochondria and their host cells is a delicate one. Both genomes evolve in very different ways. Mitochondrial genes are only passed down from mother to child, whereas the nuclear genome is a fusion of both mum’s and dad’s genes. This means that mitochondria genes evolve much faster than nuclear ones – around 10 to 30 times faster in animals and up to a hundred thousand times faster in some fungi. These dance partners are naturally drawn to different rhythms. This is a big and underappreciated problem because the nuclear and mitochondrial genomes cannot afford to clash. In a new paper, Nick Lane, a biochemist at University College London, argues that some of the most fundamental aspects of eukaryotic life are driven by the need to keep these two genomes dancing in time. The pressure to maintain this “mitonuclear match” influences why species stay separate, why we typically have two sexes, how many offspring we produce, and how we age. Dancing out of step Here’s the problem: both sets of genes help to create proteins that sit in the mitochondria and carry out one of the most important of chemical reactions: respiration. The proteins strip electrons from our food and pass them along from one to another. They eventually deposit the electrons onto oxygen; this produces water and releases energy. These ‘electron transfer chains’ are the stuff of life, and they only work if the proteins involved are built correctly. The proteins in the chain are made of different subunits. Some are built using instructions from nuclear genes, while others are built using mitochondrial genes. They different parts must fit together with nanometre precision. Even a small change in their shape will produce botched proteins that fumble their electrons. If fewer electrons make it to the end of the chain, the mitochondria produce less energy. The leaking electrons can also react with oxygen directly to produce destructive molecules called free radicals. So, cells with mismatched nuclear and mitochondrial genes face a double whammy of less energy and leaking free radicals. This has two important consequences for the evolution of eukaryotes: it creates a barrier between different species, and it favours the evolution of two sexes. Within a species, the nuclear and mitochondrial genomes have adapted alongside one another so that their protein components seamlessly fit together. These dancers don’t swap their partners easily. If different species mate, they destroy this exquisite co-evolution, which might explain why hybrids encounter so many problems. Respiration is difficult for them, their mitochondria can’t produce any energy, they’re bombarded by leaking free radicals, and many of their cells top themselves. With so many problems, it’s no wonder that many hybrids become sterile or weak, or fail to develop properly at all. This is the price of a mitonuclear mismatch. Why two sexes? Mismatches can be easily weeded out by natural selection because every individual has the same mitochondrial genome in all of its cells. Those that match up well with the nuclear genome will survive; those that match poorly will die. This weeding process breaks down if individuals have many different types of mitochondria. In this scenario, the bad matches cancel out the good ones in any individual, and everyone ends up being decidedly average. Natural selection has little to work with. Over time, individuals with a single mitochondrial genome will do better than those with many. The fittest of them will thrive thanks to natural selection, while their peers stagnate. Lane argues that one of the easiest ways of ensuring that an individual has a uniform set of mitochondria is to have two sexes. One (usually female) hands down an identical set of mitochondria to its young, and the other (usually male) doesn’t. That’s a major difference between the two sexes; some (including Lane) would argue it’s the main difference. There are species that do things differently, but they are exceptions that prove the rule. Some slime moulds have 13 different sexes, but after mating, they destroy all but one set of mitochondria. Some fungi, like baker’s yeast, inherit mitochondria from both parents, but they are quickly separated so that individual cells only contain one type. Here’s the gist: mitonuclear mismatches are easier to weed out if individuals test-drive one set of mitochondrial genes against one set of nuclear genes. And having two sexes is an easy way to do that. The death threshold The threat of mitonuclear mismatch can also explain the different lifestyles of different species. Mismatches cause a leak of free radicals and cells have two ways of dealing with that. If the leak is fairly minor, the cell can make more mitochondria to compensate. If the leak is severe enough, the cell commits suicide through a process called apoptosis. Lane’s idea is that there’s a threshold that determines which route a cell will take – a level of leakage where it chooses to cut its losses rather than fix the problem. Different species set their ‘apoptotic threshold’ at different levels. For example, birds and bats need a lot of energy to fly, and their nuclear and mitochondrial genomes must match perfectly. The proteins of their mitochondria have to shunt electrons from one to another quickly and efficiently. Even slight mistakes would compromise their energy levels, and that can’t be tolerated. So, birds and bats have very low leak thresholds. Even a slight trickle of free radicals betrays the fact that their two genomes aren’t meshing properly – time for their cells to die. Dying cells mean dying embryos, and many are eliminated before they fully develop. Only a precious few would make it through this harsh selection process. Lane thinks that this could explain why these species tend to have low fertility rates and few offspring. By contrast, a rat has less demanding energy needs, and the electron transfer chain in its mitochondria can afford to be leakier and less efficient than that of a bird. The rat can handle a poorer mitonuclear match, so it sacrifices fewer embryos on the altar of perfection. It follows that rats are also more fertile, and produce larger litters.

Even well-matched nuclear and mitochondrial genomes don’t stay that way forever. As individuals age, leaking radicals will damage and mutate the mitochondrial genome, ruining its match with the nuclear one, and causing even heavier leaks. This happens, even if the initial stream of radicals is small. As time wears on, the dancers inevitably fall out of step with each other. You can see this if you compare young and old tissues: the young cells will all have genetically identical mitochondria, while those in the old cells will be a mix of different mutants. As more cells pass the tolerance threshold, more of them die. Tissues that use the most energy, like the muscles and brain, have the heaviest leaks and wear away faster. Meanwhile, the surviving cells experience even greater energy demands. They enter a downward spiral with sweeping consequences: they leak free radicals like sieves; their DNA becomes more fragile; their genes become switched on in different ways; they release chemicals that trigger inflammation. In short, they create the perfect set-up for cancer, heart disease, diabetes, Alzheimer’s and many of the other diseases of old age. Almost all of the major traits of ageing can be predicted by a growing rift between two genomes, and a widening leak of free radicals. The leak worsens with time, so tissues die, especially gas-guzzling ones. Those that survive are more likely to become diseased. And the fast the leak, the faster all of this happens. This explains why species that tolerate less free radical leaks tend to enjoy longer lives. Consider pigeons and rats: both species are similar in both size and metabolic rates, but pigeons have far lower rates of leaking electrons in their mitochondria. They also live ten times longer. A simple idea For now, this is all a grand hypothesis, albeit one that is grounded on a lot of existing evidence. Lane now wants to explore ways of testing his idea. The most obvious first step would be to see if there actually is a lea threshold that varies between cells. It should be straightforward to measure the extent of free radical leaks in cells, and the level that makes them kill themselves. He also wants to look at species with high energy needs like birds, to see whether a large proportion of their embryos are being lost. He’s also interested in how this applies to humans. “It would be interesting to get data from fertility clinics to see if there are any groups or populations that struggle to conceive,” he says, “and if any of this can be put down to incompatibilities between mitochondria and nuclear backgrounds. Around 40% of pregnancies end in miscarriage and we don’t know why.” There is compelling majesty to Lane’s idea. At its heart, it is deceptively simple: we have two genomes that need to work together, and you can tell how well they’re doing this by the strength of the free radical leak. From that simple concept, you can logically derive how fitness, fertility and lifespan are linked in different species. You can also predict the process of ageing and the onset of age-related diseases within individuals. “A lot of this has to be true on logical grounds,” says Lane. “We know that there is co-adaptation between these two genomes and many predictions emerge seamlessly from some simple reflections on that process. The big question is whether it’s important in the greater scheme of things.” Reference:

Ageing apart

Lane, N. (2011). Mitonuclear match: Optimizing fitness and fertility over generations drives ageing within generations BioEssays DOI: 10.1002/bies.201100051

Lane, N. (2011). The Costs of Breathing Science, 334 (6053), 184-185 DOI: 10.1126/science.1214012

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