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University College London research team develops model to examine mitochondrial DNA mutations

How natural selection eliminates harmful mitochondrial DNA mutations in mammalian egg cells (oocytes) is a subject of current scientific debate and is under examination by a London university research team.


Marjorie Hecht
Oct 20, 2021

How harmful mitochondrial DNA mutations are removed in mammalian egg cells (oocytes) is a subject of current scientific debate.

It's an important question as a better understanding of the mechanism could help develop treatments for mitochondrial diseases, which are rare but deadly.

A research team from the Department of Genetics, Evolution and the Environment, at University College, London, has developed a computational and evolutionary model that sheds light on the processes involved in mitochondrial inheritance for humans and mice.

Mitochondria are energy-producing organelles that convert nutrients--sugars, fats, and oxygen--into cellular energy. The mitochondrial DNA (mtDNA) is important for determining this energy production. When the number of deleterious mtDNA mutations reaches a certain threshold, it prevents adequate energy from reaching the brain and other organs, causing devastating mitochondrial disease.

The researchers examine three hypotheses of mitochondrial inheritance and critically review the prevailing germline bottleneck idea. The bottleneck concept holds that reducing the number of copies of mtDNA to a very low number during oocyte development helps to keep the number of mutations low.

Their work appears in the journal eLife, July 19.

Mitochondrial DNA and mutations

Current Science Daily spoke with professor Andrew Pomiankowski, one of the research team, who stressed the importance of the mitochondrion organelle in all cellular processes and its potential for damaging mutations. 

"It has its own genome, and it's small but important," he said. "Its genes are only inherited maternally. They never have sex or recombination, unlike other genes in the nucleus, which are mixtures from both parents. So how do mitochondria keep themselves clean, well-adapted, and well-functioning? That's the real enigma of the mitochondria and its inheritance pattern."

Pomiankowski added, "A really weird thing about the mitochondria is that if you look at the cell nucleus, every gene is present in two copies. Whereas in the mitochondria, that's not true. In a human egg, we maybe have 500,000 of these mitochondrial DNA copies--it's a very strange and different entity within the cell. And in a normal cell--liver, brain--there's maybe 1,000 or 5,000 copies."

The number of mtDNA "has a weird effect on mutation accumulations," he said. "If maybe one or two of them are bad, who cares, because you have thousands of good ones. They'll drown out the bad."

The problem comes when the bad mutations accumulate, he said. 

"How does the cell keep the mutation numbers down? How does it keep itself nice and clean," he said. "That's the real enigma of these mitochondria and its inheritance pattern."

Keeping mtDNA bad mutations low

Pomiankowski described mitochondrial diseases as catastrophic. 

"What we know about these diseases is that you have to get up to a point where maybe half of the mitochondria are bad, for a particular gene, or 60% of them are bad," he said. "You can see symptoms before that, but maybe they're not so bad. But when you go above this level, it's really terrible."

His research group looked at how the cell keeps the number of bad mutants low, and the role of natural selection in this process. He explained that the model that most people would give is "a mitochondrial bottleneck."

"If you look at an egg cell, it starts off with about a half-million mtDNA. Then it goes through a series of divisions when the mitochondrial DNA is not replicated," he said. "That's right at the beginning of life, and it's probably because any kind of mutants early on in life would then be in all cells, so this in itself is a sort of protective device."

"You go through these cellular divisions," he added. "No mitochondrial replications are going on and you're just halving the number of mitochondrial DNAs per cell in each division. Therefore it goes from something like 500,000 down to some lower level, and as it goes down, it segregates the bad stuff into different cells." 

This will leave some cells with few mutants in their mitochondria, and when these develop as oocytes, the next generation starts from a better place.

This is the germline bottleneck model, and most people think that this is the main mechanism for mutation management, Pomiankowski said.

"Let's imagine that you went down to one mitochondrial DNA copy per cell," he added. "And if you could throw away the bad cells, the rest would be full of clean mitochondria. But the number of mtDNA in a cell doesn't go down to one. Nobody actually really knows the number--the estimate is really difficult to make. Some people say that it's around 100 or even lower, others say no, it's more like 1,000. We really don't know accurately where it goes down to. But it's thought that this is the main mechanism."

The problem with the germline bottleneck model

Pomiankowski said he's a theoretician, not an empiricist, looking at the problem. The research group's computational model found that the bottleneck theory "works to some extent" when you model a high number of mutant mtDNA copies.

"It will work quite well in terms of creating variation between the cells, and some of those cells will eventually be the progenitors of the next set of eggs, some of which are better, some of which are worse," he said. 

This comes through a process of natural selection, which will reduce the number of bad mutations.

"But it doesn't work very well if you already have quite a small number of mtDNA copies," he said. "Because by the time you've done 10 rounds of cell division, you've created as much segregation variation as you're going to generate. And yet it takes more on the order of 40 or 50 rounds of cell replication before you've got another egg cell."

The bottleneck theory "doesn't do a very good job of explaining what we actually see, that's the bottom line," Pomiankowski added. "The distribution of mutation number in the human population appears to be too low and it doesn't make a lot of sense in terms of this bottleneck idea. It can't really explain the data very well."

What the germline bottleneck model ignores "is that people have been so fixated on this idea that they thought they had an explanation," he noted. "I think what the modeling says is that explanation doesn't really fit the data; it can't explain the data in itself. 

"We're not saying that this doesn't happen," Pomiankowski said. "It happens. We can see that you go from 500,000 [mtDNA] down to some lowish number and then you go back up again eventually. But that in itself is not enough to explain the distribution, the rareness of these mitochondrial diseases in nature."

Other elements that could cause mtDNA mutations

Pomiankowski said that his group's model could not "resolve the empirical estimates better."

"Most researchers have assumed that the bottleneck is the dominant force restricting the spread of deleterious mtDNA mutations," he said. "Our work suggests other forces are important as well."

In particular, he noted the selective transfer of mitochondria in the Balbiani body.

Balbiani bodies are clusters of mitochondria and other organelles, seen in cells which develop into oocytes. In humans a cyst of several nurse cells form and stream their mitochondria into the Balbiani body in a single primordial oocyte.

Recent evidence suggests that only mutation-free mitochondria make it across. The nurse cells left with higher numbers of mutant mtDNA then undergo apoptosis-- programmed cellular death. 

"The modeling shows that this selection at the level of individual mitochondria really has a strong cleansing effect," Pomiankowski said. "Better measures of this are needed. As the Balbiani body is a common feature of most multicellular eukaryotes, it opens up experimenters to look in non-vertebrate model systems, for instance in the fly Drosophila and worm C. elegans. Work there should be a lot easier than in humans, where experimentation is impossible and gathering of data is very difficult."

Future work

Where does the research go from here?

Pomiankowski said: "My own interest is in the strange evolutionary patterns seen in mitochondria. Genes in the mitochondria have very different patterns of transmission than the normal genes found in the nucleus. The mitochondrion is a relic of an ancient symbiosis, and was originally an independent bacterial cell. It was incorporated early in the evolution of the eukaryotic cell as an energy-producing organelle but never evolved to be part of the normal sex and recombination process which helps keep genes in the nucleus free from deleterious mutations."

This means "other mechanisms had to evolve to maintain mitochondrial function, originally in unicellular organisms and now in multicellular organisms with differentiated germlines and proper sexes," he said. "This is where my interests lie."

Marco Colnaghi et al., The need for high-quality oocyte mitochondria at extreme ploidy dictates mammalian germline development, eLife, 07-19-2021,DOI: 10.7554/eLife.69344

https://elifesciences.org/articles/69344


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