The Quiet Wars of Mitochondria

It is difficult to believe in the dreadful but quiet war of organic beings, going on in the peaceful woods and smiling fields.

— Charles Darwin

Every week for one of my courses at NYU Biology, the first-years meet a different professor from the department to dissect a paper and design hypothetical follow-up studies. This week’s paper (more on this later) cast mitochondria in a new light for me. On top of other recent work on mitochondria, it also made me realize that mitochondria (alongside chloroplasts) are wonderfully equipped to demonstrate several key evolutionary principles.

Mitochondria are tiny, energy-producing compartments – formally described as organelles – found inside all cells containing a nucleus, but there is more to them than that. More than a billion years ago, the earth was exclusively inhabited by bacteria and archaea, single-celled organisms whose cells lack compartments and complex organization. According to the widely accepted endosymbiotic theory, mitochondria are thought to have originated when a bacterial cell that was captured by an archaeal cell as food managed to avoid getting digested. Over time, the enslaved bacterial cell took over the energy-generating function of its captor and became the mitochondria we know today. How can we tell? For one thing, the mitochondria still carry some of their own DNA – the instructions for life carried by all organisms – and it resembles the DNA of existing bacteria.

The domestication of the mitochondria and its coevolution with its captor led to the origin of the eukaryotic cell, with its nucleus and other myriad compartments, which makes up organisms ranging from the single-celled amoeba to plants and animals. In their new sequestered abode inside a cell, the mitochondria found themselves in the midst of multiple modes of conflict.

During sexual reproduction in plants and animals, the male gamete (sex cell) fertilizes the female gamete to form the single cell that will give rise to the whole organism. The male gamete contributes half of the male parent’s DNA, while the female gamete contributes half of the female parent’s DNA along with the whole cell including all the mitochondria. This is why the offspring inherits mitochondria only from the mother. The mitochondria – which you may recall carry their own DNA – that the offspring receives from its mother are basically identical to the ones that the mother received from the offspring’s grandmother.

Why is this a problem? Evolutionary biologists call it Muller’s ratchet:

DNA, when it gets copied, can accumulate mistakes, which are called mutations. Most mutations mess up the instructions that the DNA is supposed to pass on, and are therefore harmful to the organism. If individuals in a population reproduce asexually, they will all eventually accumulate harmful mutations in the absence of a way to get rid of them. This is known as Muller’s ratchet, named after the scientist who came up with the concept and a device that only turns in one direction. Sexually reproducing organisms mix-and-match the maternal and paternal halves of their DNA before passing on half of their total DNA to their offspring. This process, known as recombination, provides a way of not passing on a harmful mutation to the offspring. Bacteria, which reproduce asexually, generally solve this problem by recombining frequently with DNA from their environment which often come from dead, identical bacteria from the same population. They  can replace harmful mutations in their DNA with non-harmful versions from their immediate environment.

Mitochondria in such organisms exist as small populations with limited diversity of DNA sequences inside cells. While they frequently recombine with each other, that does not help them avoid Muller’s ratchet as any harmful mutation that occurs would remain as part of the population of mitochondria inside a cell. How then do the mitochondria avoid accumulating harmful mutations? Or more precisely, how do these organisms stop the mitochondria they rely on from accumulating defects?

Now, we do have a stake in this question. Mitochondria carrying harmful mutations cause severe neurological and muscular diseases in humans due to problems with energy production. Maybe that’s why we rarely see defective mitochondria, because individuals carrying them die or have lower reproductive fitness. But given that individuals with mitochondrial defects are relatively rare, there must be another way in which harmful mutations are weeded out from mitochondrial DNA.

As it turns out, mitochondria undergo purifying selection, whereby mitochondria with harmful mutations and therefore lower fitness are purged, during female gamete formation. This is significant as the mitochondria inside female gametes are the only ones that are passed on to the next generation.

Mitochondria ordinarily fuse together to form clumps inside cells. The paper I mention at the beginning elegantly demonstrated using fruit flies that the fused mitochondria fragment and separate during female gamete formation (but notably not during male gamete formation), and the mitochondria containing DNA with a harmful mutation are outcompeted by the mitochondria containing normal DNA. Further experiments suggest that female gamete cells actively select against less fit mitochondria, and that defects in energy generation possibly allow for this selection. Animals, at least, appear to have figured out a way to keep their mitochondria healthy by pitting them against each other. It will be interesting to see how generalizable this mechanism is across sexually reproducing organisms. To my knowledge, it is also not well-understood how the handful of exclusively asexual eukaryotic organisms that exist take care of this problem.

Mitochondria, however, are not just ridiculously docile pets, happy to undergo brutal purges when asked. In sexually reproducing organisms, they have a conflict of interest with the organism that carries them when it comes to the different sexes. While selection at the level of genes shared by males and females favors equal sex ratios (the study I’ve linked is an experimental demonstration of this), mitochondria face selection to drive female-biased sex ratios as they are only passed on through females. For the same reason, mitochondrial mutations that increase maternal or female fitness would be selected even at the cost of lower fitness of males.

Evolutionary biologists have identified several cases in plants where mitochondrial DNA evolved to cause male sterility, which would be expected to result in more more females in the population with time. These events are generally followed by the evolution of suppressors of sterility in the plant’s own DNA in its nucleus; otherwise, the organism would go extinct if all males were wiped out. This supports the idea of an arms race resulting from the conflict between mitochondrial and nuclear DNA, or mitonuclear conflict.

Interestingly, mitonuclear conflict has been suggested to play a role in speciation. Imagine two populations of the same species that have been separated. The mitochondria evolve to bias their own transmission independently in the two populations, which is followed by each population undergoing changes in its nuclear DNA to counter its particular set of mitochondrial mutations. At the end of this process, the mitochondria of each population would likely be incompatible with the nuclear DNA of the other. This in turn would reduce the fitness of hybrids of individuals from the two populations as half of their nuclear DNA would be from a different population than their mitochondria. Such hybrid incompatibilities have been inferred in studies on multiple species (here’s one).

Conflicts drive the accumulation of genetic differences

In some organisms, like yeast, where mitochondria are transmitted by both parents to the offspring during sexual production, there is opportunity for recombination between the DNA from the two mitochondrial populations, providing a way of avoiding Muller’s ratchet. Crucially though, this also provides an opportunity for conflict between mitochondria from the two parents. Mitochondria have been shown to evolve to bias their own transmission when in competition with other mitochondria. This can result in conflict with the nuclear DNA as well, as these cheater mitochondria may come at a functional cost to the organism; for instance, they may replicate faster but produce less energy.

Mitochondria represent fascinating case studies of two prominent themes in modern evolutionary biology: intragenomic conflict, which is conflict between DNA elements found within a single organism, such as mitonuclear conflict; and selection at multiple levels, demonstrated by within-organism selection of mitochondria in developing female gametes and between-organism selection against mitochondrial mutations that cause disease and lower fitness in individuals. For an organelle with a violent origin in the midst of a predator-prey conflict, it is perhaps not surprising that mitochondria remain perpetually entangled in these quiet wars.

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