Mitigating Mutational Meltdown in Mammalian Mitochondria

October 19, 2012 3:21 AM

Mitigating Mutational Meltdown in Mammalian Mitochondria PLoS Biol 6(2): e35. [The PDF, where you can read the paper in its much prettier intended format.]

Mitochondria are remarkable microorganisms. About two billion years ago, their distant free-living ancestors hooked up with a truly foreign lineage of archaebacteria and started a genomic merger that led to the most successful coevolved mutualism on the planet: the eukaryotic cell. Along the way, evolving mitochondria lost a lot of genomic baggage, entrusted their emerging hosts with their own replication, sorted out genomic conflicts by following maternal inheritance, and have mostly abstained from sex and recombination. What mitochondria did retain was a subset of genes that encode critical components of the electron transport chain and ATP synthesis enzymes that carry out oxidative phosphorylation. Because mitochondria house the biochemical machinery that requires us to breathe oxygen, it was first assumed that mitochondrial genes would show very slow rates of molecular evolution. So it was big news almost 30 years ago when mitochondrial DNA (mtDNA) evolution was observed to be quite rapid ^[1]. How could the genes for a highly conserved and critical function sustain the consequences of high mutation pressure and permit rapid rates of nucleotide substitution between species? Without the benefits of recombination, where offspring can carry fewer mutations than either parent, mutations should accumulate in mitochondrial genomes through the random loss of less-mutated genomes, a process referred to as Muller's ratchet ^[2,3]. How have mitochondria avoided a mutational meltdown, or at least significant declines in fitness?

Here is a jaw droppingly beautiful 3D animation of what Mitochindria look like in action.

A quick explanation of Muller's Ratchet by MetaFilter's own Scientist

posted by Blasdelb (37 comments total)

and have mostly abstained from sex and recombination

Mostly?
posted by delmoi at 4:33 AM on October 19, 2012 [1 favorite]

Warning: the animation does not work unless you have a fast connection. Cells and YouTube adapt to their environment, xvivo.net does not.
posted by EnterTheStory at 4:37 AM on October 19, 2012

Holy Fuck.

G-d exists. And THIS is what he creates. Are we really so self centered to think He gives a shit what we do to keep busy as long as the ATP keeps dancing?
posted by mikelieman at 4:38 AM on October 19, 2012 [1 favorite]

No alliteration tag?
posted by knile at 4:40 AM on October 19, 2012

"Mostly?"

It depends on how you look at it, a better meaphor would probably be to call Mitochondria cross species monogomists. Where they prolifically exchange genetic material with their host cells but not meaningfully with other mitochondria.
posted by Blasdelb at 4:45 AM on October 19, 2012 [1 favorite]

We are made up of trillions of little factories, staffed with molecular robots. Also, I work across the hallway from Dr. Lue. He's a nice guy, made up of trillions of little factories, staffed with molecular robots.
posted by not_on_display at 4:48 AM on October 19, 2012 [8 favorites]

" G-d exists. And THIS is what he creates. Are we really so self centered to think He gives a shit what we do to keep busy as long as the ATP keeps dancing?"

While I personally feel that the why's of this sort of thing are best understood using a Creator as a metaphor to understand the representational kinds of truths, like with a parable, the how's of it all are perfectly well understandable without the use of a creator at all - hell its much much easier to. That video, and this paper, were made from a purely mechanical understanding of the universe strongly informed by evolutionary principles.
posted by Blasdelb at 4:52 AM on October 19, 2012 [2 favorites]

"Without the midichlorians, life could not exist, and we would have no knowledge of the Force. They continually speak to us, telling us the will of the Force. When you learn to quiet your mind, you'll hear them speaking to you."

Oh, wait, you said mitochondria! Sorry.
posted by crossoverman at 5:13 AM on October 19, 2012 [3 favorites]

the animations are wonderful! thank you.
posted by mareli at 5:15 AM on October 19, 2012

the animations are wonderful! thank you.

I think so too, and I've made two large collections of all of the ones I've found,

The beauty of Molecular, Cell, and Microbiology

Animating Medicine
posted by Blasdelb at 5:35 AM on October 19, 2012 [6 favorites]

Fantastic animation but I would love to have some kind of narration/annotation to understand what I was looking at.
posted by antiwiggle at 5:48 AM on October 19, 2012 [1 favorite]

Related: Minding Your Mitochondria, a TEDx talk by Dr. Terry Wahls. A compelling argument for optimal mitochondria health through diet.
posted by yoga at 5:49 AM on October 19, 2012

Fantastic animation but I would love to have some kind of narration/annotation to understand what I was looking at.

The youtube link " critical components of the electron transport chain and ATP synthesis enzymes" in the post explained it to me fairly well. Been a long time since undergrad bio.
posted by mikelieman at 5:54 AM on October 19, 2012 [2 favorites]

G-d exists. And THIS is what he creates.

But isn't the universe in which this sort of thing arises gradually and naturally out of chaos without the active intervention of a willful tinkering creator god a lot more interesting? Needing a watchmaker god for everything that's cool just seems like a massive failure of imagination to me, an arbitrary imposition of anthropomorphizing master metaphor, eliding over most of the not-quite-countless interesting steps in the process of development.
posted by aught at 6:23 AM on October 19, 2012

entrusted their emerging hosts with their own replication

I'm just a layman who thinks cells are awesome, but this is the part that blows my mind. How do you go from "I'm in ur cytoplasm processin ur molecules" to "oh yes, while you're at this reproducing thing, why don't you go ahead and make more of me too, but let's still make it look kinda like I swam in from outside and set up shop in a pocket inside you." It's like tapeworms changing your DNA so that your babies are born with tapeworms inside them—instead of like, with tapeworm fingers (you're welcome for these mental images). Time to read to try to understand it.
posted by fleacircus at 6:29 AM on October 19, 2012 [3 favorites]

These animations are really fun, but beware the false sense that they are actually depicting what is going on. It is a lot easier to get macromolecular structures and render them than it is to be definitive about the interactions that are going on. Essentially you are seeing an interaction that is to what goes on in a cell what The Sims is to human relationships.
posted by andorphin at 6:30 AM on October 19, 2012 [6 favorites]

"beware the false sense that they are actually depicting what is going on"

This is very true. For one, the cell is so densely packed with molecules that getting a clear view of these organelles would be virtually impossible. The inside of a cell isn't water with an occasional protein floating around - it's a freaking slurry.
posted by chrisamiller at 7:20 AM on October 19, 2012 [5 favorites]

" . . . beware the false sense that they are actually depicting what is going on."

Also, most of these molecules are smaller than the wavelengths of visible light, which leaves them without color.

But if they did have colors, these would be nice ones. :)
posted by Phyllis Harmonic at 7:24 AM on October 19, 2012 [2 favorites]

G-d exists. And THIS is what he creates.

When fundamentalist Christians insist that God created us directly, they strike me as denigrating their own deity.

Assume that you believe in a God who wanted to create us. It has two ways of accomplishing it. It can point the omnipotent Finger and then... POOF! There's a guy.

Or It can create the conditions allowing a primordial soup to accumulate, maybe apply the subtlest english of a nudge to create a single self-replicating organism, and then sit back and wait a few billion years while evolution does all its colorful stuff and eventually produces some Jews that provide a suitable vehicle to take the next Step.

Doesn't the latter method seem far more stylish? A more imaginative filling in of the canvas of eternity?
posted by Egg Shen at 7:25 AM on October 19, 2012 [7 favorites]

Or It can create the conditions allowing a primordial soup to accumulate, maybe apply the subtlest english of a nudge to create a single self-replicating organism, and then sit back and wait a few billion years while evolution does all its colorful stuff and eventually produces some Jews that provide a suitable vehicle to take the next Step.

Doesn't the latter method seem far more stylish? A more imaginative filling in of the canvas of eternity?

There's a bit in a book I read as a kid -- I so wish I could remember it -- in which, as an aside, the author says something like, "Lots of people talk about the miracle of turning water into wine. But just as miraculous, when you think about it, is the process of turning sunlight into wine by means of a few grapes and a chemical process, and that's a miracle that happens every day."
posted by gauche at 7:29 AM on October 19, 2012 [4 favorites]

Also, most of these molecules are smaller than the wavelengths of visible light, which leaves them without color.

The amino acid tryptophan does fluoresce with a peak emission at ~325 nm and extends into visible wavelengths. So one could say that the closest thing to a protein color is violet.
posted by euphorb at 7:46 AM on October 19, 2012 [1 favorite]

the process of turning sunlight into wine by means of a few grapes and a chemical process

Saccharomyces cerevisiae also plays a pretty big role in this particular miracle.
posted by en forme de poire at 7:52 AM on October 19, 2012 [2 favorites]

"... the process of turning sunlight into wine by means of a few grapes and a chemical process"

"Saccharomyces cerevisiae also plays a pretty big role in this particular miracle."

Botryotinia fuckeliana, aka Botrytis cinerea- does a pretty miraculous thing to grapes, too.
posted by Phyllis Harmonic at 8:01 AM on October 19, 2012 [1 favorite]

"Also, most of these molecules are smaller than the wavelengths of visible light, which leaves them without color."

This is not quit true. looked at with a light microscope almost all proteins cannot be seen, they would show up as a blur, but thqt blur would hqve a color. Looking at things smaller than the wavelength of visible light with visible light is kind of like trying to probe a keychain bobble with a broomstick, you do get data, but it doesn't really mean much. (By contrast using an electron microscope would be like using a toothpick)

However, at least for looking at color, you can indeed look at a whole lot of proteins at the same time proteins and look at the color of the blur you get. When you do this, concentrated complex mixtures of proteins, like what you'd get in the interphase of a nucleic acid extraction, are pretty much always a milky opalescent white.
posted by Blasdelb at 8:09 AM on October 19, 2012 [1 favorite]

crossoverman: ""Without the midichlorians, life could not exist, and we would have no knowledge of the Force. They continually speak to us, telling us the will of the Force. When you learn to quiet your mind, you'll hear them speaking to you."

Oh, wait, you said mitochondria! Sorry."

There was a period of about three or four years after I'd learned about cell biology but before I'd been officially introduced to the Star Wars fandom when I was constantly really, really confused about why everyone who was into Star Wars seemed to hate mitochondria so much. I mean, yeah, they're a little annoying to draw on tests and making a 3D version that looks half-decent for your science fair project takes forever, but surely that's not deserving of such loathing.
posted by Phire at 8:11 AM on October 19, 2012 [1 favorite]

As I suspected, it says nothing about the farandolae.

did not read tfa
posted by no relation at 9:07 AM on October 19, 2012 [2 favorites]

"This is very true. For one, the cell is so densely packed with molecules that getting a clear view of these organelles would be virtually impossible. The inside of a cell isn't water with an occasional protein floating around - it's a freaking slurry."

If this is something that interests you, I'd like to point you towards the art of David Goodsell who is a molecular biologist at Scripps that creates beautiful and amazingly precise illustrations of the inside of cells.

This conumdrum is apparently one of the frustrations of molecular animation, when Drew Berry (A particularly awesome and prolific molecular animator) stopped by here a while ago he talked about it. He also once experimented with showing at least some of the slurry.
posted by Blasdelb at 9:23 AM on October 19, 2012 [1 favorite]

" . . . are pretty much always a milky opalescent white."

Well, OK- but Rayleigh scattering is not the same as the inherent color of the material, which is what I was referring to. I should have been more specific.
posted by Phyllis Harmonic at 9:32 AM on October 19, 2012 [1 favorite]

It seems to me (and, I am sure, others, including those who actually know something about biology) that the origination of eukaryotic life (i.e. all plants and animals), was an unlikely event, one that suggests that us two legged eukaryotes might indeed be very very lonely in this big universe. The universe may well be teaming with life on other planets - just that it's single celled life.
posted by not_that_epiphanius at 9:40 AM on October 19, 2012

If excess polymorphism is a common pattern, then molecular clock approaches that infer age of the most recent common ancestor in humans will be overestimates

The problem of overestimation is solved by using two molecular clocks, the Y-chromosome haplogroups in addition to mitochondrial haplogroups.
posted by francesca too at 11:12 AM on October 19, 2012

That 3-D animation is spectacular! All these visual aids make learning the dry boring stuff much easier.
posted by francesca too at 11:18 AM on October 19, 2012

It seems to me (and, I am sure, others, including those who actually know something about biology) that the origination of eukaryotic life (i.e. all plants and animals), was an unlikely event, one that suggests that us two legged eukaryotes might indeed be very very lonely in this big universe. The universe may well be teaming with life on other planets - just that it's single celled life.

I have little to no opinion on how "likely" eukaryotes are, but there are multicellular prokaryotes.

G-d exists. And THIS is what he creates.

This and ebola!
posted by Flunkie at 11:40 AM on October 19, 2012 [1 favorite]

He also once experimented with showing at least some of the slurry.

This animation was really cool. Not as visually striking as the one in the OP, but I appreciated the explanation of what was going on.
posted by kjh at 12:44 PM on October 19, 2012

its now 2012: sooo... How have mitochondria avoided a mutational meltdown, or at least significant declines in fitness?

These guys observe evidence of positive "purifying" mutations, but dont mention any actual mechanism. Is this the million dollar question in mitochondria genetics? (because, erm... yknow, it does have the whiff of intelligent design until someone figures it out....)
posted by dongolier at 2:06 PM on October 19, 2012

Thanks for this, it's right in my wheelhouse as we do a lot of this sort of work in the lab where I work. More recently we've moved to microsatellite datasets and we're going to be doing a lot of SNP work very soon, but some of the older projects (which are still churning out new information and new papers) in the lab are with mtDNA.

Speaking specifically to fleacircus's question, (it's a really excellent question) the question of how mitochondria managed to get their host cells to perform their replication for them is a really interesting one and the answer is touched on in the linked article and a little bit in comments, but I'll spell it out a bit more: bits of mitochondrial DNA have a tendency to migrate into the nucleus of the cell and become what are known at NUMTs, (NUclear-MiTochondrial) which may get integrated into the nuclear genome and continue to function and make their corresponding proteins and such despite not being in their original locations. Over time this process has led to a reduction in the size of the mitochondrial genome as more and more of it has become integrated into the host cells' nuclear genomes.

This process has lots of advantages for the mitochondria (and for the cells that depend on them) and one of them bears directly on the subject of the article in the FPP. Integration into the nuclear genome is one of the mitochondrion's defenses against mutation, because mitochondrial genes that get moved into the nuclear genome mutate at a slower rate thatn those in the mitochondrial genome (proofreading is better in the nucleus) and can undergo recombination during meiosis to remove deleterious mutations without having to necessarily also throw out the entire genome that they are attached to, which is a problem that mitochondria otherwise have to deal with (and which is the main subject of the article in the FPP).

The discovery of NUMTs also wreaked a bit of havoc in evolutionary biology a while back, because as the article mentions mitochondrial DNA gets used a *lot* (not as much now, but still a lot, and for a good while it was the genetic-material-of-choice) in the construction of evolutionary trees and many of the statistical tools that are used for doing so depend on having a decent idea of how fast a particular sequence is likely to mutate. If you are analyzing a sequence that you think is mitochondrial but which is actually a NUMT, then your mutation rate is all wrong and your phylogenetic tree isn't going to come out true. That is the kind of thing that keeps evolutionary biologists up at night.

Thanks for this article, Blasdelb. Your recent series of molecular bio FPPs has been phenomenal and I really hope you keep it up because I am absolutely loving it.
posted by Scientist at 5:17 PM on October 19, 2012 [1 favorite]

Oh, I should add (I mentioned it above but I glossed over it) that critical to the process of mitochondrial->nuclear DNA migration is the fact that it can be a highly beneficial process both to the host cell and to the mitochondria, because it increases the stability of the mitochondrial genome and also improves the ability to preserve adaptive mutations and remove deleterious ones.

That is why it happens and that is why the host cells have taken over so many of the mitochondria's functions: it is good for both of them, because they both depend on each other and by and large the nucleus of a cell is better at handling DNA than the mitochondria are. So it makes sense for all the cell's DNA to be there if possible, including mitochondrial DNA.

That leads to the question of why, if it's such a great thing for mitochondrial DNA to be in the genome, do mitochondria still have any genome at all? I won't get into that right now (partly because I suspect I am not really qualified to do so in an effective and accurate way) but it just goes to show how curious and complicated the relationship between mitochondria and eukaryotic cells is.
posted by Scientist at 5:23 PM on October 19, 2012

mutations should accumulate in mitochondrial genomes through the random loss of less-mutated genomes

Answer -- like everything in biology, it's not actually random. Just because there's no grant vision in the sky doesn't mean all changes are equally likely.

Random is hard, and unless it's absurdly advantageous, is not going to be expensively selected for.
posted by effugas at 3:54 AM on October 20, 2012