Capacitance Hypothesis for Mitochondrial Mediated Aging.
The capacitance hypothesis can be summarised as follows:
Mitochondria are electronic devices analogous to electrolytic capacitors.
As mitochondria age they become increasingly uncoupled ( ie they leak charge) most probably through the mediation of the uncoupling proteins (UCPs). Mild, partial, progressive uncoupling results in a decrease in maximum power, slower recharging (to the required threshold pre-discharge voltage) and a diminished energetic capacity. Full depolarisation results in apoptosis (cell death).
Genetically programmed uncoupling through UCP variations provides a simple basis for a mechanism for determining life span.
Background: Mitochondria, acting at the cellular level are central both to the aging process and the final onset of senescence. Below are four (uncontroversial) statements supporting this assertion:
Mitochondria produce free energy, in a chemical form, which is used to drive metabolism and this ‘energy’ decreases with age.1
Supergeriatric humans (lifespans > 100) when compared to ‘normal’ humans (lifespans <90) show no differences in nuclear DNA (nDNA)2in whole genome analysis but do show variations in mitochondrial DNA (mtDNA)3
Mitochondria become progressively uncoupled ( electronically leaky) with age4,5,6: supergeriatrics v normal humans show age-related differences in so called uncoupling proteins (UCP1-4) which regulate mitochondrial ‘leakiness’.7
Animals with highly coupled mitochondria ( eg bats, pigeons) live proportionately longer lives than animals of equivalent size that do not ( eg bats v mice 20yrs v 2yrs)11
Fifty years ago my research12 was led by the first of the bullet points - we notice with ageing that we have less energy!. Since that time fifty years ago, technological developments have enabled genome sequencing and rapid structural analysis of proteins but has disappointingly yielded very little progress on the fundamental driving processes of aging. Telomer shortening and free-radical damage13 theories have come and gone in this time, but steadily little by little the focus has shifted back towards the mitochondrion. So much so that as I write mitochondrial underperformance is being asserted as causal in Alzheimer' s brain deterioration14
Presented here are novel mechanisms for the gradual age-related changes in mitochondrial function, consistent with the facts above, and consistent with experiential changes of aging which are well known to all of us. Additionally, as a corollary, a mechanism for the variation in the life span of mammals is proposed based on a hypothetical determinant mediated by mitochondria.
Mitochondria as electrical devices:
Mitochondria have all of the characteristics of the free-living creatures; that is their biology, physiology, and biochemistry are complex and under the influence of the normal cellular processes from biosynthesis/destruction to reproduction and signalled controls.
I wish to focus here though on one neglected ( I think) aspect of their nature: electronics. This possibility, the electronic nature of mitochondria, came to be a possibility as soon as the transmembrane potential( ie a voltage, symbol ΔΨ ) was recognised following Michell’s Chemiosmotic15 proton gradient theory over 60 years ago.( For this article protons (H+) themselves somewhat mythical beasts, are treated as anti-electrons, analogous to electron holes in the semiconductor world). To date, as far as I can read, the electrical engineers have not had much input into this field, which I hope to rectify (pardon the pun). As a result I am not differentiating in an electronically meaningful way between proton gradients and other ionic gradients. I am just interested in charge separation, electron rich and electron poor regions, or positive ion rich or positive ion pore, separated by a barrier with a known dielectric; it’s all the same.
In this document, mitochondria are regarded primarily as electrical devices, in that they use electrons ( via ion pump proxies) to generate membrane potentials (voltages) and have capacitance ( the ability to store charge) proportional to the surface area and dielectric of the inner mitochondrial membrane. The energy stored by these mini-capacitors is used, in batches, analogous to capacitor discharge, to liberate the Gibbs’ free energy which in turn is used to drive metabolic processes which require it ( for example the synthesis of ATP from ADP and Pi which requires by the way 73 joules of free energy.).
As with capacitors used in the world of electronics, the devices ( mitochondria in this case) have a time-based charging curve, a rapid discharge curve, a dielectric constant based on the lipid composition of the inner membrane, a total capacitance and a charge-leakage profile.
Diagrams:
The diagrams below show a mitochondrion charging through a supply of electrons from oxidisable substrates then rapidly discharging as a threshold inner membrane potential is reached sufficient to generate ATP ( or other phosphorylated nucleotide such as GTP).
The y-axis is related to free-energy, and is comprised of the classical equations linking16 voltage and capacitance to free-energy*. The x-axis is time (T), It can be seen that the charge and discharge of a mitochondrion occurs over time as a near square wave.
The frequency of discharge then determines the energy expended per unit of time, that is it is power(P) output of the mitochondrion. The height of the discharge wave is related to the amount of energy stored
and so is capacitance(C).
Figure 1:
A set of charge-discharge curves for a mitochondrion-capacitor showing showing increasing levels of charge
leakage (uncoupling). It takes increasingly longer to reach the required membrane potential for a given supply
of substrate-derived electrons/protons. Ultimately the threshold potential will not be reached and then
mitochondria will depolarise triggering apoptosis.
Figure 2:
A series of charge’discharge curves as energy is drawn off the mitochondrion in response to demand.
The rate at which work (charge/discharge) can be done is a measure of the power output of the mitochondrion.
The red lines represent the charge/discharge curves of an older ‘leakier’ mitochondrion.
Less power is available.
Power output.
The diagram in Figure 2 shows the ‘beat’ of a mitochondrial power curve.
Mitochondria are known to oscillate over a range of time periods,
slow being 4 minutes and faster 20 seconds17.
Mitochondrial cytochromes can also absorb light in the NIR range at about 800nm this is at TeraHz frequencies!18
Capacitance notes:
For a given supply of substrate-derived electrons/protons the time to reach the required membrane potential depends on the magnitude of the capacitance ( ie amount of energy that can be stored) and the amount of charge leakage. A smaller capacitance would be an adaptive response to a mitochondrion that is struggling to reach the membrane potential threshold for ATP synthesis.
Possible uncoupling mitigation strategies:
An adaptive response to uncoupling as threshold voltages become harder to reach would involve a decrease in the surface area of the inner mitochondrial membrane in order to reduce energetic capacity but still be viable in the production of ATP. Other mitigating strategies could involve a decrease in the dielectric constant of the inner membrane by changing the lipid composition and/or stimulation of mitochondrial activity by substrate supplementation ( eg acetyl-carnitine, malic acid). Mega mitochondria often obserevd in senescent cell with fewer internal cristae probably represent an attempt to stay viable though in a low power state16.
Ref:
1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18
