The problem of poise

Let's think back again to how respiration works. Electrons and protons are stripped from food, and react with oxygen to provide the energy that we need to live. The energy is released a bit at a time, by breaking the reaction into a series of small steps. These steps take place in the respiratory chain, down which electrons flow, as if down a tiny wire. At several points the energy released is used to pump protons across a membrane, trapping them on the other side, like water behind the dam of a reservoir. The flow of protons back from this reservoir, through special channels in the dam (the drive shafts of the ATPase motor) powers the formation of ATP, the energy 'currency' of the cell.

Let's consider briefly the speed of respiration. Everything is coupled like cogs, so the speed of one cog controls the speed of the rest. So what controls the overall speed of the cogs? The answer is demand, but let's think this through. If electrons flow quickly down the chain, then the protons are pumped quickly (for proton pumping depends on electron flow) and the proton reservoir 'fills up'. A full reservoir, in turn, provides a high pressure to form ATP quickly, as protons flow back through the dedicated drive shaft of the ATPase. Now think what happens if there is no demand for ATP. In Chapter 4, we saw that ATP is formed from ADP and phosphate, and when it is broken down again, to provide energy, it reverts to ADP and phosphate. When demand is low, ATP is not consumed by the cell. Respiration converts all the ADP and phosphate into ATP, and that's that: the raw materials are exhausted, and the ATPase must grind to a halt. If the ATPase motor is not turning, then protons can no longer pass through the drive shaft. The proton reservoir brims full. As a result, protons can no longer be pumped against the high pressure of the reservoir. And without proton pumping, electrons can't flow down the chain. In other words, if demand is low, everything backs up and the speed of respiration slows right down until fresh demand starts all the wheels turning again. So the speed of respiration ultimately depends on demand.

But this is what happens when everything is working well and the cogs are well greased. There are other reasons for respiration to slow down, and these are not related to demand but to supply. We have noted one instance: the supply of ADP and phosphate. Normally, the concentration of these raw materials reflects the consumption of ATP, but it is always possible that there is simply a shortage of ADP and phosphate. Then there is the supply of oxygen or glucose. If there is not enough oxygen around—if we are suffocating—electron flow down the chain must slow down because there is nothing to remove the elec trons at the end. They are forced to back up in the chain, and everything else slows down just as if there were a shortage of ADP. What about glucose? Now the number of electrons and protons that enter the chain is restricted—as if we were starving—so the flow of electrons is forced to slow down, which is to say the volume of electrons flowing down the chain per second falls.

So, the overall speed of respiration should ideally reflect demand, which is to say consumption of ATP, but under difficult conditions, such as starvation or suffocation, or perhaps a metabolic shortage of raw materials, then the speed of respiration reflects the supply rather than the demand. In both cases, however, the overall speed of respiration is reflected in the speed that electrons flow down the respiratory chain. If electrons flow quickly, glucose and oxygen are consumed quickly, and by definition, respiration is fast. Now, after this little detour, we can return to the point. There is a third factor that causes respiration to slow down, and this relates neither to supply nor demand, but rather to the quality of the wiring: it relates to the components of the respiratory chain themselves.

The components of the electron-transport chains have a choice of two possible states: they can either be oxidized (they don't have an electron) or they can be reduced (they do have an electron). Obviously they can't be both at once— they either have an electron or they don't. If a carrier already has an electron, it can't receive another one until it has passed on the first to the next carrier in the chain. Respiration will be held up until it has passed on this electron. Conversely, if a carrier doesn't have an electron, it can't pass on anything to the next carrier until it has received an electron from an earlier carrier. Respiration will be held up until it receives one. The overall speed of respiration therefore depends on the dynamic equilibrium between oxidation and reduction. There are thousands of respiratory chains in a single mitochondrion. Respiration will proceed most rapidly when 50 per cent of the carriers within these chains are oxidized (ready to receive electrons from an earlier carrier), and 50 per cent are reduced (ready to pass on electrons to the next carrier). If the rate of respiration is plotted out mathematically, it fits the equation of a bell curve. Respiration is fast at the top of the bell curve and slows precipitously on either side, as the carriers become more oxidized or reduced. The point of optimal balance, the top of the bell curve at which respiration is fastest, is known as 'redox poise'. Straying from redox poise slows down energy production, and such inefficiency, as we have seen, is strongly selected against in bacteria.

But the penalty for straying from redox poise is worse than inefficiency: there is the devil to pay. All the carriers of the respiratory chain are potentially reactive—they 'want' to pass their electrons to a neighbour (they have a chemical propensity to do so). If respiration is progressing normally, each carrier is most likely to pass on its electrons to the next carrier in the chain, each one of which

'wants' the electron a bit more than did its predecessor; but if the next carrier is already full then the chain becomes blocked. There is now a greater risk that the reactive carriers will pass on their electrons to something else instead. The most likely candidate is oxygen itself, which easily forms toxic free radicals such as the superoxide radical. I discussed the damage caused by free radicals in Oxygen; here, the important point is that free radicals react indiscriminately to damage all kinds of biological molecules. Formation of free radicals by the respiratory chain has influenced life in profound and unexpected ways, including the evolution of warm-bloodedness, cell suicide, and ageing, as we'll see in later chapters. For now, though, let's just note that if the chain becomes blocked, it is more likely to leak free radicals, just as a blocked drainpipe is more likely to spring water from small cracks.

So there are two good reasons for sustaining poise: keeping respiration as fast as possible, and restricting the leak of reactive free radicals. But maintaining poise is not just a matter of keeping the correct balance of electrons entering the respiratory chains to those leaving at the other end: it also depends on the relative number of carriers within the chains, and this fluctuates because the carriers are continually replaced, like everything else in the body.

Let's think about this for a moment. What happens if there aren't enough carriers in the respiratory chains? A shortage of carriers means that the passage of electrons down the respiratory chain slows down, just as too few links in a human bucket chain means there is a slow supply of water getting to the fire. Such a slow transfer of water to the fire equates to a shortage of water: even if the reservoir is full, the house will burn down. Conversely, if there are too many carriers in the middle of the chain, these accumulate electrons faster than they can be passed on down the chain. In the bucket chain analogy, the buckets are being passed faster at the beginning of the chain than at the end—there is a build-up in the middle and everything goes haywire. In both cases, respiration slows down because there is an imbalance in the number of carriers in the respiratory chains, not in the levels of any raw materials. If the concentration of any of these carriers gets out of kilter with the requirements of respiration, respiration slows, and free radicals leak out to cause damage.

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