Monday, October 28, 2013

The human machine: non-standard components

The previous post in this series can be found here.

In a previous post I alluded to the origins of mitochondria, the tiny chemical power plants found within all our cells. These hard-working machines are responsible for aerobic respiration, which is the way in which the vast, vast majority of the energy you use is released from the chemical energy in the food you eat. The way in which they do this is very cool, involving currents of electrons and protons in a manner very similar to standard battery. If you're interested in this then I direct you to my earlier post on this topic here, but in this post I will be discussing a rather odd thing about mitochondria: they're not in fact human...

What do I mean by this? Well, obviously they are, kind of, human since they're inside all of us, they're born with us and die with us, they don't wander off on their own to live an independent life elsewhere. Nonetheless, mitochondria are different to the rest of the machinery in our cells - they have their own genomes, they regulate their own replication, they make proteins their own unique way - in fact they closely resemble lifeforms that we might consider to be evolutionary polar opposites of ourselves: bacteria. That sounds pretty odd, right, that there might be bacteria living inside our cells that somehow want to help us by churning out energy for us to use? Seems pretty implausible, but there is a mountain of evidence supporting it.

If it barks like a bacterium...

Firstly, mitochondria do, kind of, look like bacteria. They are about the right size to be bacteria (0.5-1 micron in length) and have internal structures similar to many bacteria. The main difference is that mitochondria possess two membranes and no cell wall, whereas most bacteria for one membrane and a robust cell wall. The inner membrane of mitochondria is also far more ruffled than most bacteria, creating a much larger surface area - this is highly important for reasons that I'll come to!

Spot the difference: mitochondria on top, bacteria on the bottom. 

Looks are by no means everything, though, and it is when you start to investigate the molecular components of mitochondria that you really see the parallels with bacteria. The most obvious of these is that they have their own DNA, and I don't mean that they have their own copies of the human DNA in the cell nucleus - they have their own genomes. They are the only human organelle (i.e. a component of the cell) to have non-nuclear DNA. An early explanation for this was the autogenous hypothesis, in which a bit of the nuclear DNA somehow split off from the main genome during the early evolution of eukaryotes (species with a cell nucleus - including all multicellular organisms - all of which also contain mitochondria), which then was engulfed by its own membranes and became semi-autonomous. However, this doesn't explain why the mitochondrial genome is highly similar to genomes seen in bacteria. Firstly, eukaryotic nuclear DNA is linear - i.e. it has a start and an end - whereas both bacterial and mitochondrial DNA is circular in most species. Secondly, its means of replication is more similar to bacterial DNA than human. Thirdly, many mitochondrial genes are highly similar to those present in some bacteria.

Aside from their unique genome, there are several other aspects of mitochondrial biochemistry that point to a bacterial origin. Mitochondria make their own proteins: normally proteins are synthesised in the endoplasmic reticulum by molecular factories called ribosomes before being transported to wherever they are needed in the cell. Mitochondria not only have their own ribosomes, but their ribosomes are far more similar to those found in bacteria than in eukaryotes - termed '70S' due to their smaller size than the '80S' ribosomes in eukaryotes. These mitochondrial ribosomes also work in a different way to eukaryotic ribosomes. All eukayotic proteins start with the amino acid methionine, whereas bacterial proteins start with N-formylmethionine. Proteins made in the mitochondria start with, you guessed it, N-formylmethionine. The membranes of mitochondria contain the lipid cardiolipin, which is only otherwise found in bacteria. These membranes also contain several types of protein that are not present in the membranes of eukaryotes but are in bacteria, such as porins. Mitochondria also divide by a process known as binary fission, in a manner very similar to bacteria but distinct from eukaryotic cells. 


So, in short, there is very good reason to believe that mitochondria are, or at least were, bacteria. In which case - why the hell are they in our cells? Generally being invaded by bacteria is not a good thing, we've evolved a beautifully intricate immune system to prevent just that very thing happening, what's gone on here? Well the fact of the matter is that we would never have got to the level of sophistication that we have without the metabolic help of our mitochondrial invaders. The reason for this goes back to the surface area issue that I mentioned earlier. All bacteria convert chemical energy in food into other forms by means of a proton gradient across a membrane - i.e. there are more protons on one side than the other, like water running down a waterwheel. This is the same process used by mitochondria (as described previously) and was almost certainly the way we (by which I mean the single-celled eukaryotes that eventually evolved into us) also did things. This is an elegant and efficient means of converting energy, but it has a fundamental limitation - the rate of energy conversion is directly proportional to the surface area of the membrane; i.e. a larger membrane area allows more energy to be converted in the same time compared to a smaller area. This is a problem as cells get bigger since larger cells have a smaller surface area to volume ratio and so the rate of energy conversion at the membrane struggles to keep up with the increased demands of the larger cell. Thus, cells cannot go beyond a certain size before their energy needs outstrip their supply.

As dimensions increase, the surface area to volume ratio of a cell decreases.

This is an issue when it comes to evolving increasing levels of sophistication. Features such as mutlicellularity and the evolution of complex organisms requires cells to have complex signalling pathways that coordinate behaviour as well as large genomes to provide the molecular diversity to allow complexity. This all takes up space in the cell, and a bacteria-size cell just isn't going to cut it. Bacteria can perform feats of metabolic magic that larger organisms can only dream of, but these are just simple chemical reactions rather than coordinated signalling systems and, crucially, they don't require much space. Bigger is better as far as cellular complexity is concerned, yet, as described above, cells can't get too big without falling victim to their own energetic needs, so how to overcome this?

The answer is to relieve the cell's dependence on the surface area of its membrane for energy generation. This can be done by relocating the source of energy conversion to other sites within the cell that contain  large, folded areas of membrane that are then capable of generating enough energy to power the cell. This is where mitochondria come in. Because mitochondria have highly ruffled internal membranes they have a vast membrane area over which proton gradients can be generated, and are able to release energy at a much greater rate than the cell could on its own. Moreover, since many mitochondria can be packed into a single, large cell (up to 2000 in human liver cells, for example), the cell has plenty of energy to spare and so can start to undertake processes that would otherwise be impossible - such as costly chemical reactions or physical processes such as muscle contraction. Without the abundance of energy afforded to cells by mitochondria, the vast majority of processes that we undertake, at both a cellular and organismal level, would not be possible. So, there is a very good reason why we need mitochondria and why we should be grateful to our bacterial passengers!


Of course saying that something would be useful does not mean that it will happen or indeed that it is even possible. So how did mitochondria get into our cells in the first place, and is that even a feasible concept? Well in fact the process of endosymbiosis - in which one organism lives inside another - is fairly common throughout biology. Many plants house bacteria in their roots that process nitrogen to fertilise the plant, whilst some fish cultivate bioluminescent bacteria that allow them to glow in order to evade predators or attract prey. In these cases the bacteria are not, strictly speaking, part of the larger organism as they simply live within specialised areas, a bit like the bacteria that live in your gut, but the concept of endosymbiosis on a cellular level is really no different. 

What seems to have happened, is that around 2.5-3 billion years ago, when the very first eukaryotic cells were evolving, somewhere an oxygen-using proteobacterium somehow ended up inside one of the early wave of eukaryotic cells. We don't know whether it was the eukaryotic cell that did the engulfing (perhaps trying to 'eat' the bacterium) or whether the bacterium was trying to invade the eukaryote, but we do know that something usual occurred. Rather than either the bacterium being consumed by the eukaryote or the eukaryote being devoured from the inside by the bacterium, the bacterium managed to survive inside the larger cell and begin dividing. In its new home it was pretty safe - it was protected from attacks by other bacteria and didn't have to work hard to find food as the eukaryote did that for it. This is basically what intracellular bacterial parasites do now - they find their way into the cells or larger organisms and camp out there having a great time at the expense of the host. 

However, this initial endosymbiosis was not entirely parasitic. If it had been then that early eukaryote would have been at a significant evolutionary disadvantage and would surely have perished, never to be seen again. It is possible that this was the fate of the vast majority of eukaryotes that ended up containing the early ancestors of mitcochondria. Eventually, though, one lucky cell managed to find a balance with its passenger bacterium such that, rather than being a parasite, the bacterium was now a useful ally. This may have arisen because of a defect in the bacteria such that it started leaking its energy (in the form of the molecule ATP) into the larger cell. Normally this would be extremely bad for the bacterium, but in this case it may have been useful as it gave its host an energetic advantage that allowed it, and so the bacterium, to thrive. Once this symbiotic relationship had been established there was no looking back. This lucky cell went on to dominate all of eukaryotic evolution and eventually diversify into all multicellular organisms, including all animals, fungi, and (with the help of another bacterium that would become the chloroplasts) plants.

Endosymbiosis of mitochondria and chloroplasts throughout evolution.

As host and bacterium evolved together, the symbiotic relationship became more and more deeply entrenched. The eukaryote eventually lost its ability to generate energy at its cell surface, opting instead to rely wholly on its bacterial passengers. In return, the bacteria began to evolve into a more streamlined energy factory - developing ruffled membranes to maximise surface area, and forgoing many functions that were now undertaken by the host, such as locomotion - and so began to resemble the mitochondria we possess today. In time, many of the genes encoded by the bacterial genome would be relocated to the cell nucleus, but many would remain in order to ensure the efficient synthesis of proteins important to mitochondrial function in the mitochondrion itself rather than having to wait for them to be transported from the endoplasmic reticulum. The mitochondria also began to become more tightly tied into the newly evolving process of multicellularity. Perhaps most strikingly, they became central to the process of cell death (apoptosis - see my earlier post here), a prerequisite for the evolution of large organisms. 

Today, the relationship between mitochondria and processes dictated by the nucleus is extremely tight, though the signs of their bacterial origins are still clear to see. In many ways they are still not fully part of our cells: they divide semi-independently and undergo different patterns of inheritance (you only inherit your mother's mitochondria, not your father's). It's fascinating to think that we are not wholly 'human' in as much as being 'human' is a feasible concept anyway. What's also very cool is that we can quite accurately map which bacteria our mitochondria are related to, and so in a way identify our nearest bacterial cousins. It turns out that mitochondria are most closely related to bacteria within the order Rickettsiales. Appropriately these are mainly obligate intracellular bacteria, meaning that they generally live within the cells of other species. One genus within this order - the Rickettsia -  can infect humans and cause the well-known disease typhus. In fact many of the most closely related bacteria to mitochondria - within the family Anaplasmataceae - are also capable of causing nasty diseases in humans, including anaplasmosis and erlichiosis. It is only through a quirk of evolutionary fate that our mitochondria developed into vital parters rather than debilitating invaders!

The position of mitochondria within the family tree of alphaproteobacteria - from Williams et al. (2007).

The story of mitochondria is a fascinating one, and one that I cannot do justice to here, though I hope I have given you an appreciation for how flexible and unpredictable biological evolution can be and how considering humans distinct from this is both incorrect and arrogant. There are many books on the subject of mitochondrial evolution, but the best that I have come across is 'Power, Sex, Suicide: Mitochondria and the Meaning of Life' by Nick Lane, which is a great read. If you don't get a chance to read it, just remember one thing: the human machine is far from human.

The next post in this series can be found here.

Kelly P. Williams, Bruno W. Sobral, and Allan W. Dickerman (2007). A Robust Species Tree for the Alphaproteobacteria Journal of Bacteriology DOI: 10.1128/JB.00269-07


  1. I can imagine an awesome Planet of the Apes type of moment in the allegorical novel of the human immune system when the protagonist civilisation realise that their entire energy manufacturing system arose from a collaboration in the distant past between their ancestors and a close relative of their arch enemies.

    I might have written that before.

    How did the Eukaryote and Bacterium know to divide at the same time? (i.e. when it came time to reproduce how did the children cells end up with the bacteria in both of them?) Or is it just a case of this happening millions of times and the one time that the reproduction somehow triggered each other would be the "fittest" and thus the survivor to today?

    1. Yeah, it would rock them to their core and there would be a big divide between those who think that the ends justify the means and the moral purists! This novel is getting more and more awesome.

      I'd imagine that at first they didn't know how to divide at the same time, but if you imagine that if the eukaryote divides and one daughter cell doesn't contain any of the pseudo-mitochondria then it will lose its advantage and so die out. Only the ones that kept the bacteria would keep thriving. Over time the mitochondria will have evolved to coordinate their division with events in the larger cell that indicate general cell division, such as the abundance of certain proteins and metabolites. You're absolutely right, though, that this will have happened billions and billions of times and only the small number of cells that had the optimum set-up will have out-competed the others to dominate the eukaryotic domain - that's just how micro-evolution works.

  2. Fascinating... I had no idea...
    Nicely written - Thank you James.

    So if I grasp this correctly; Humanity owes their existence to bacteria that owe their existence to humanity...

    Now perhaps I read too quickly (and I do need to read the "back story") but are these mitochondria "species specific" or do all living creatures benifit from common mitochondria cousins?

    1. Thanks, Masodo. You're quite correct - we could not exist without mitochondria and they would probably have died out without us!

      As for the species-specificity, all multicellular organisms evolved from the same single-celled ancestor, and the incorporation event with mitochondria happened before that - so we all share mitochondria from the same ancester bacterium. That's not to say they are the same, though, as they've evolved independently over the last several billion years and so are individually adapted to the biochemistry of their host organisms. Interestingly, many organisms have additional bacterium-derived organelles that merged with them after their split from the human evolutionary lineage (such as the plastids), so we can map these events fairly accurately in evolutionary time.


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