So far in my series of posts, I’ve tried to give you an appreciation for how war is fought on a microscopic level, which is to say: how invading pathogens try to consume our body’s resources, and how our immune system fights back. In my last post, I also tried to convey some of the contemporary research that is expanding our understanding of this system. While this is (to me at least!) a fascinating topic, I am going to put it to one side for the time being. The reason for this is that there are just so many enthralling topics to talk about when it comes to molecular biology! So, I have decided to concentrate a new series of posts on various interesting snippets of biology and biochemistry that I hope you will find intriguing and allow you to understand your own body a little better. In doing this, I don’t want to lose sight of the purpose of this blog – i.e. to convey a sense of the ongoing work taking place – and so will try to include cutting-edge research into each post whenever possible.
Preamble over, let’s get started...
Looking deeper and deeper
‘How does my body actually work?’ It’s a question that’s likely occurred to most of us at some point in our lives. Most people know how our skeleton is arranged and how our muscles tug at various parts of it to allow movement; similarly we all know how our hearts pump blood around this vast system, and what our various internal organs do. But science is all about finding something out and then saying ‘sure...but how does that work’ and then taking it down to the next level. When physicists discovered protons and neutrons, they weren’t content to leave it there; they took it to the next level and found out what those are made of, and then what the things they’re made of are made of, and so on to the present day. The same is true for biology – sure your muscles contract, but what are they made of, how do they contract and where do they get the energy from? It is this last point that we will deal with today: where does our body get energy from?
The simple answer to the above question is just: food. We all know we need to eat to have energy; if you’re a bit of an athlete or diet-enthusiast then you might know about the different components of food (carbs, fats, protein etc.) and how they affect the body. But have you ever wondered how all those varieties of different foods end up powering your body at the molecular level?
How much is that? ATP! (pause for laughter)
The system by which we are powered is staggeringly beautiful in its construction and efficiency. It runs every second of your life unwaveringly and faultlessly, and would do so forever if the more fragile components of our bodies didn’t eventually throw us over the edge of this mortal coil! The problem that must be overcome by our bodies (to which I alluded earlier) is that we eat all sorts of different molecules in our food, yet our cells must always work the same way. The way to get around this is a kind of cellular bureau de change, where the various currencies of the different foods are exchanged for a single energy currency that is good for use anywhere in the body. This single ‘currency’ is called ATP (or adenosine triphosphate if you want the full name), and is perhaps the most important single molecule in your body. ATP is used by almost all active processes that take place in your body; some of these are obvious, such as muscle contraction, but the vast majority take place in relative anonymity. There’s no possibility that I could list all of the myriad events that take place in every cell in your body that are powered by ATP; they range from alcohol metabolism in the liver, to light receptor recycling in the eye, to production of antibodies in B cells. In short, you use ATP for almost everything you do, including every thought and memory that you have, since ATP gives the energy to transmit signals down every neuron in your brain.
|Adenosine Triphosphate. 80p, you say?|
All of these processes devour ATP and break it up into its components ADP (adenosine diphosphate) and inorganic phosphate, so your cells are constantly sticking these two components back together to keep you supplied with ATP. If your body suddenly stopped making ATP (as happens with some poisons, as we’ll see later) then you would die within seconds. In fact, ATP is in such demand that even though there is only 250g of it in your body at any one time, you make roughly your entire body weight fresh every day, only for it to be used to up keeping you alive. This is equivalent to the energy released by roughly 1kg of TNT (i.e. 4.2 megajoules for a 70kg human), which means that over the course of a 70 year life you process enough ATP to release the equivalent energy of more than two GBU-43/B Massive Ordnance Air Blast Bombs (i.e 107,000 MJ, or around 25.5 tonnes TNT). It is, to put it lightly, quite important.
While that’s all very interesting, I want to explain to you how ATP is made and how we convert all of our food into this single, vital molecule. If this is your first foray into bioenergetics then you might be somewhat taken aback to learn that we actually run on electricity; which is to say is it the generation of an electric current within our cells that allows the production of ATP, which in turn powers everything we do. In fact, the principle behind our own power is identical to that behind how energy is released from a standard battery! Better than that, in fact, we run on two types of current! If you’re not familiar with the details: electrical current is the movement of subatomic particles called electrons down an electrical potential - i.e. they move from where there are lots of electrons, to where there are few electrons. They do this because they are negatively charged and so repel one another and try to move apart if at all possible. Protons, on the other hand, are positively charged subatomic particles. Protons are (as Shaun can tell you in far greater detail than I) more complex than electrons but the overriding principle is the same: they will try to move apart because they all have like (positive) charges. We run on two currents; the first is an electrical current, the second is a proton current.
Anything you eat, whether it’s carbohydrate, fat, protein, or other molecules, enters into your general metabolic network. This is a vastly complex series of chemical reactions whereby the structures of the various food molecules are shaped and changed into a small number of metabolic ‘standards’ that can be easily exploited for energy. I’m not going to go into the details of this now, it’s far too large a topic to cover here, but hopefully the figure below gives you some idea of just how vast and intricate this system is!
|General metabolism - don't strain your eyes!|
Throughout this whole process, the energy released by these chemical reactions is used to stick protons onto two key molecules: NAD (nicotinamide adenine dinucleotide) and FAD (flavin adenine dinucleotide), to make NADH and FADH2, respectively. These are the molecules that power the electrical current that I mentioned earlier. NADH and FADH2 travel to specific structures in the cell called mitochondria where the whole process of ATP production begins.
Fully charged: mitochondrial lighting!
Mitochondria are fascinating things; they used to be separate organisms that lived independently as single-celled life forms, but were one day engulfed by a larger cell and formed a symbiotic relationship that has served them well and exists to this day. An artefact of this is that they still have some of their own genes in their own mitochondrial genome, and their own systems of DNA replication and protein production.
|A stranger turned ally - mitochondria power our cells.|
Mitochondria have an intricate internal structure, but the bit that is important for ATP generation is the ‘inner mitochondrial membrane’. A number of proteins are inserted into this membrane to form what is known as the mitochondrial ‘electron transport chain'. Four of these are responsible for converting the electrical current into a proton current, and are helpfully referred to as complexes I to IV. Complexes I and II are the entry points for NADH and FADH2, respectively. Complex I removes two electrons from NADH, converting it back into NAD and releasing it, while Complex II takes two electrons from FADH2, releasing free FAD. These electrons travel through the proteins in short hops between electron-binding sites formed by metal ions conjugated to the protein backbone, such as the common Iron-Sulphur clusters. This is analogous to the movement of electrons down a copper wire to power a light bulb or some other electrical device. However, unlike the free flowing electrons in the wire, the electrons in complexes I and II are only able to move from one site to the next within the protein because of the phenomena described in quantum electrodynamics, which allow electrons and other subatomic particles to move over short distances without passing through the space between. This is necessary in the electron transport chain because there are often no direct routes from one site to the next, and so the electrons have to be forced to hop along the chain by the electrons behind it being released by NADH orFADH2. It is intriguing to imagine that the fundamental physics of a quantum world so alien to everything we perceive is the basis of the most important process that takes place within our bodies!
|Mitochondrial electron transport (complex II not shown; protons shown as H+)|
Both complexes I and II pass their gained electrons on to a molecule known as coenzyme Q that continues the steady march of the electrical current running through the mitochondrial membrane. However, complex I has an added role; during the movement of electrons through its structure, its shape is contorted and re-set over and over again. These shape changes cause it to act as an electron-driven pump that moves protons from one side of the membrane to the other via subtle changes in the environments of trapped water molecules. In total, complex I transports 4 protons from the mitochondrial matrix into the intermembrane space for every NADH that it processes. This is the first step in the production of a proton current over the membrane that will ultimately drive ATP synthesis.
The role of coenzyme Q is a complex one that I don’t want to discuss in too much detail here. Briefly, its job is to deliver the electrons on to complex III, but in doing so to move yet more protons over the membrane. It does this by a process known as the ‘Q cycle' in which it sequentially gains protons on the matrix side of the membrane and then loses then on the other. This moves even more protons up the gradient that is forming over the membrane.
|The Q cycle|
The electrons continue their march along the chain through complex III and into complex IV via an intermediate electron-binding protein called cytochrome c. Four molecules of cytochrome c bind to complex IV sequentially and donate their electrons to a central site where they await their final destination. In this centre, the electrons are finally donated onto a waiting oxygen molecule, which splits and forms two water molecules by snapping up protons from the matrix side of the membrane. Ever wondered what the oxygen you were breathing in was actually doing? Well this is it – it acts at the final electron acceptor in the mitochondrial electron transport chain. Moreover, the reaction also results in the uptake of protons from the matrix side of the membrane, and the dumping of other protons out into the intermembrane space. Cyanide and carbon monoxide both inhibit this final reaction and so kill you stone dead because the final electrons in the chain can’t be lost and so the whole thing backs up, meaning no proton pumping and so, as we’re about to see, no ATP production.
The motor: ATP synthase
So, we’ve seen so far how the electrical current running through our mitochondria is used to pump protons from one side of a membrane to another, but what use is that for making ATP? Well, as I said earlier, protons don’t want to be crammed next to each other because of their repelling positive charges. If there are more protons on one side of the membrane that the other, then they are going to want to cross it, and work energy can be extracted by letting them do so. It’s the equivalent of pumping water to the top of a water tower and then extracting work energy from its fall back to earth under gravity. In this case, the work energy will be used to make ATP by a truly remarkable protein complex called ATP synthase.
|Round, and round, and round she goes: where she stops, ATP comes out!|
ATP synthase is a collection of proteins (hence the term ‘protein complex’) that harnesses the energy released by the movement of protons from the intermembrane space to the mitochondrial matrix and uses it to make ATP. It does this by acting, quite literally, as an engine, with moving components driven by a current. The key to this is its structure. ATP synthase has a ring component embedded within the membrane that is capable of spinning independently of the rest of the complex. Protons move through this ring in order to get back to the matrix and, for reasons I won’t go into, so cause the ring to spin furiously at up to 7000 revolutions per minute! The spinning ring is attached to another component of ATP synthase called the gamma subunit, that spins with the ring. The gamma subunit in embedded within the centre responsible for ATP production, called the alpha-beta complex. As the gamma subunit spins, it causes the alpha-beta subunit to change shape, since this does not spin. The shape changes cause alpha-beta to cycle through a series of stages where it binds ADP and Pi, then catalyses their conversion to ATP, then releases ATP, then begins again. And so, the movement of the ring in the membrane drives the synthesis of ATP by alpha-beta. It is a wonderfully elegant machine that whirs constantly in every cell in your body and powers everything you do.
ATP synthase in action - courtesy of YouTube
I hope this has been an interesting post and that I've given you some insight into the beautiful engineering that makes up the technological marvel that is your body! Each post in this series will look at a different under-appreciated aspect of how your body works, so if there's anything in particular that you'd like me to focus on then please let me know!
The next post in this series can be found here.