Overclocking Mitochondria.
‘Overclocking’ is a concept well known to computer-game enthusiasts. Simply put, they can increase the performance of their computer by speeding up the CPU ( central processing unit) or the GPU (graphics processing unit) by increasing the clock speed (instruction-cycles per second). They do this essentially by upping the voltage supplied to the chips … upto and including the point where they becomes too hot and inevitably unstable. Typically, such voltages are between 3 and 5 volts and CPU cycles run at many MHz (million cycles per second). The ‘free’ extra performance is much prized by ‘overclockers’ with equally serious cooling systems and a penchant for breaking things.
Mitochondria have somethings in common with CPUs. They too are cycle driven electronic devices; their cycle is called (variously) Kreb’s Cycle, the TCA cycle or the Citric acid cycle. As it cycles, it fetches acetyl ‘food’ molecules from its surroundings spewing out waste water, carbon dioxide and heat as it makes ATP: magical, universal, ATP. ATP in turn is used to provide the free energy needed to drive all negative-entropy biological processes such as synthesis, repair, nervous conduction and locomotion. It makes over 100 ATP molecule per second which is about 3Hz in computer parlance* It does this with normal (trans-membrane) voltages between 110 and 150 mv ( 1/10th of a volt), 140mv being associated with optimum ATP efficiency.
Overclocked mitochondria, like CPUs fall into two categories; working well under conditions of high demand and just broken. The former would be the case say for substrate-stimulated mitochondria using molecules such as glutamate and malate which speed up the TCA cycle and raise membrane potentials to 180mv. The latter would be for example hyper-polarised mitochondria found in cancer cells. These do not produce any ATP at all and are effectively inactive. They have membrane potentials of 220 mv, over ⅕ of a volt. This is put in perspective when 200 mv is usually recognised as the upper limit supported by lipid bilayers before breakdown as a result of exceeding the dielectric capacity.
Computer CPUs and mitochondria, not unexpectedly work best in their ‘Goldilocks zone” just the right amount of volts! With regard to mitochondria, very low membrane potentials, flrting with depolarisation are associated with cell death, enlarged mitochondria and fewer cristae. The opposite seems to be the case, higher membrane potentials are associated with smaller mitochondria with many cristae … and possibly with the inhibition of cell death whic intriguingly this may be the ‘motivation’ of the cancer cell’s hyper-polarisation of mitochondria thereby turning off the mitochondria’s ability to kill a rogue cell.
Exploring The Goldilocks Zone
We can downregulate (or even destroy membrane potential) and speed up the cycle by increasing metabolic demand or by using natural or exogenous uncoupling agents. These include the natural uncoupling proteins (UCPs) and chemicals like DNP ( dinitrophenylhydrazine) … too much of these will uncouple the mitochondria and cause complete collapse of potential … followed by cell death.
Conversely, membrane potential can be increased by stimulation (without extra metabolic demand) using substrates such as malate and glutamate salts or as mentioned earlier by blocking ATP synthesis.
If we assume operating at a level of metabolic demand which reflects good levels physical activity, nervous activity and tissue repair activity, it would be good if our mitochondria were operating above minimum ‘tick-over’ thresholds ( 108mv). Otherwise this would mean that increasing demand further on these mitochondria might depolarise them ... with disastrous effects. A capacity to work hard should be reflected best in the 150-180 mv range, probably the higher the better. We know that cancer cells can achieve massive potentials of over 200mv when blocking metabolic activity but it’s not clear whether such overpotentials can be utilized when oxidative metabolic demands are being made, even so stimulated mitochondria that have not been uncoupled will show potentials of 180mv.
We also know that animals with lots of brown fat, the cells of which are thermogenic because they contain partially uncoupled mitochondria, also have longer life spans than those of a similar size (cf squirrels @ 20 years, bats @ 30 years). In these animals mitochondria typically still manage membrane potentials of 140 mv despite being partially uncoupled . Their cycles are running very quickly but generate heat rather than coupled to the generation of ATP
Finally we also know from the work of Bruce Ames a decade ago that stimulation of mitochondria with acyl-carnitine ( which will increase the cycles and membrane potential as for malate and glutamate) and they associated the stimulation with increased cognitive behaviour in aged rats.
As an aside they added lipoic acid to ‘mop up’ excess free radicals. This point is worth expanding on. Free radical production by highly active mitochondria was once the bogeyman in the aging world. Free radicals cause damage to proteins and DNA which thens needs repair/replacement. Free radical damage accumulation is still one of the most popular aging theories. My point of view is that all damage can be repaired if there is the free energy so to do. In effect this means if you have enough ATP available then repair is not an issue. It’s an entropy thing. So in other words, free radical damage that accumulates with age reflects a repair-free energy deficit not a damage surfeit. This is borne out by the fact that it has been well established that higher metabolic rates ( ie higher free radical damage) correlates not with lower life spans but longer.
So, keeping mitochondria spinning within their goldilocks zone seem to be the trick. In an oxidative environment where ATP production is not blocked there seems to be no downside to high membrane potentials. However there is one fly in the ointment and that is mitochondria in poor condition need to be destroyed so they they do not divide and compromise the total cell population of mitochondria. This, as has been explored in a previous blog, is achieved through autophagy which in turn is stimulated or signaled by low mitochondrial membrane potentials.
Outside the Goldilocks Zone
So far so confusing, what about outside of the Goldilocks Zone? Ultra high membrane potentials can be dealt with quickly. They can only be produced in intact, mitochondria in good condition and reach their maximum when metabolic demand is at zero. Like the pressure in a water line, it is at a maximum when the tap is closed. Otherwise they seem to be harmless. Low potentials on the other hand have major effects.
Complete depolarisation, the collapse of the membrane potential, usually results in the release of cytochrome c from the inner membrane of the mitochondria triggering the cascade of reactions that lead to cell death. It looks like flickering depolarisation may act as a signal or a label for autophagy. This potentially is a ‘good thing’ in that sub-standard mitochondria will be eliminated from the population. A flickering state could be triggered by high metabolic demand. For example in bats, which have exceptionally well coupled low ROS mitochondria have ultra long life spans of 30 years, remarkable for such a small mammal (cf rat @ 3 years), they only develop these mitochondria after they start flying: in other words after extreme oxidative metabolic demands are made.
Anoxia, ( low oxygen tension at altitude for example) causes both mitochondrial depletion and hyperpolarization. High altitude training of athletes results in fewer mitochondria within muscle cells but those that remain are better coupled.
Summary
Like many before me I am getting lost in the woods as it were. My overclocking analogy does not really hold for very long. CPUs cycle at a clock rate proportional to voltage but independently of external load whereas mitochondria behave more like simple electric motors which cycle according to voltage and load, according to work done. What has worked though is an exploration of mitochondrial voltage, it looks like there is an optimal voltage and cycle rate which generates enough ATP to keep the system working with an excess of free energy.
I think that mitochondrial stimulation and energetic loads must be important in preventing senescence, finding the sweet spot is the challenge.
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