Mitochondrial morphology and Ageing
The possible effects of mitochondrial inner membrane surface area to volume ratios on their electrochemical capacity.
Synopsis:
I argue that age-related enlargement of mitochondria accompanied by a loss of internal folding (christae) is a morphological response to progressive inner membrane porosity and represents an attempt to maintain ΔΨ at a threshold level needed to synthesise ATP. A corollary of this effect is to reduce teh capacity of a mitcohondrion to produce a sustained flow of energy, a characteristic of old age itself.
The argument is made by modelling mitochondria as simple electrical capacitators which in circuits perform the role of energy supply, storage and regulation (smoothing).
In my Ph.D thesis of 1980 I reported the, now well documented, appearance of larger than normal mitochondria with diminished internal christal folding (1) in the liver cells of senescent rats. I hypothesised then as now that this would have an effect on the charge separation across the membrane known as the membrane potential ΔΨ.
Mega mitochondria, as they are called, are often observed in cells just prior to apoptosis (2,3) and so it is reasonable to propose that this kind of morphological change has biological significance.
In this article I will propose that the enlargement of of mitochondria is an adaptive response to age-related energetic stress which has the effect of maintaining, in a situation of increased leakage of charge, a trans-membrane potential high enough to provide sufficient free energy for the synthesis of ATP.
A corollary of this change is that larger mitochondria with fewer christae, although able to produce ATP, have a lower capacity to generate it continuously in proportion to their reduced membrane area. In other words they 'get tired' more rapidly than their younger counterparts.
In order to explain my proposal I have adopted a simple electronic model of the mitcohondrion as a charge storage device known to all as the capacitor. The mitochondrion-as-capacitor has much in common with the simple electronic capacitor. As with a capacitor a mitochondrion has a membrane potential measured in volts, a flow of charge measure in coulombs and a charge capacitance measured in farads. Like the foils and insulators in a capacitor the mitochondrial membrane has a measurable dielectric constant and like the capacitor it leaks away charge at a rate determined by its membrane integrity and dielectric constant.
Finally like the capacitor, the free energy stored by the mitochondrion obeys the Nernst equation and is thus a function of the degree of charge separation ( potential difference) and the total surface area over which the charge is separated. With all of the above mind I have created a model that demonstrates that the capacity of a mitochondrion to generate ATP depends critically on the surface are to volume ratio of the inner mitochondrial membrane.
The Mitochondria as Capacitor
It has been my view for 35 years that mitochondria should be regarded as bio-electrical charge storage devices which can be 'tapped' for stored free-energy on demand via the agency of the ATP-synthetase complexes.
I see them as mini mobile capacitors insulated from each other and their surroundings by high-dielectric outer-membrane ' shielding wrappers', racing from place to place within the cell to where demand is highest or arranged in arrays as batteries to power muscles or joining together to form high capacity reticulate structures surrounding the nucleus during cell division as energy stores.
I also see the emergence of enlarged mitochondria with fewer christae in-folds in ageing cells as a sign that they are struggling to keep their charge high enough to have sufficient threshold free energy to synthesise ATP. As they age mitochondria produce increased amounts of free radicals (4) a sign of decreased structural integrity of the inner mitochondrial membrane which I also see as an increase in the rate at which charge is being lost from the membrane. This is analogous to the 'charge leakage' of a capacitor.
I found no evidence from my own research that aged rat liver mitochondria were unable to produce ATP (5) as well as younger mitochondria but it is important to appreciate, that as with electronic capacitors, a potential difference will be maintained at a level set by the rate at which charge is supplied minus the rate at which charge is being lost. It's the old problem of filling a bath with the plug out. How fast is it filling, how big is the bath and how fast is it flowing out? The diagrams below illustrate how I imagine this works.
A water analogy for mitochondrial capacitance where H measures the 'head of water' needed to produce sufficient pressure (ie voltage V ) to produce free energy for ATP synthesis. X is the rate of supply of electrons from substrates metabolised by mitochondria; y is the rate of leakage or loss of charge and z is the rate of production of ATP.
A water analogy for mitochondrial capacitance where H measures the 'head of water' needed to produce sufficient pressure (ie voltage V ) to produce free energy for ATP synthesis. X is the rate of supply of electrons from substrates metabolised by mitochondria; y is the rate of leakage or loss of charge and z is the rate of production of ATP.
The water analogy follows the Nernst equation in all respects; the key variable in the visual analogy being H the 'voltage' required to make ATP. It can be seen that the rate of filling and leaking of the bath will determine how quickly H is reached. ATP can then be drawn off at a rate that does not allow H to fall below its critical value.
It should be clear that the rate (z) at which ATP can be drawn depends on the difference between filling and leaking ( x-y) once H has been reached. If y increases or x decreases for whatever reason, as long as x>y, then the critical value of H can be reached.
However crucially it is reached much more quickly if the capacitance of the bath is reduced.
In the above: E is the free energy needed to synthesise ATP; R,T and F are respectively the Gas Constant, the absolute temperature of the system and the Faraday Constant. What is left is the charge transferred (z) and the potential difference in Volts between the inner and outer sides of the mitochondrial membrane
Older larger mitochondria with fewer cristae have a smaller surface area to volume ratio than their highly folded younger counterparts. This means that as with an electrical capacitor they will more readily reach their working voltage when supplied with charge but will have a lower capacitance and thus less total energy ( measure in Joules) available to do work.
Also, the proportion of the stored energy that has the threshold voltage needed to synthesis ATP will fall very rapidly as the charge is drawn off. Energy in joules is the product of the voltage ( across the membrane) and the amount of electrons or available charge measure in coulombs.
The equation below summarises the relationship as described for a conventional electronic capacitor.
Joules = volts x coulombs
This relationship in my model also defines the basic energetics of a mitochondrion.
Discussion
While a cell remains viable the mitochondria maintain sufficient electrical integrity to provide the membrane potential needed for the synthesis of ATP. Cell death, apoptosis, is preceded by the loss of membrane integrity leading to leakage and loss of potential. As they age mitochondria are able to compensate for membrane deterioration by morphological changes.
My assertion is that by becoming bigger with fewer christae they are are able to maintain a critical membrane potential despite a higher leakage of charge. The trade off is a sacrificing of capacity leading to the characteristic loss of energy in old age. Support for this idea is provided by modelling a mitochondrion against an electronic capacitor which would behave in an identical manner.
As a corollary it is possible to see the mitochondrial outer membrane less as a nondescript wrapper, a boundary and no more for the mitochondrion to become a more active component analogous to the shielding wrappers of electronic capacitators.
Outer membranes are particularly responsive in their composition to diet. High cholesterol diet increases the concentration of cholesterol in the outer membrane (9) and hence its dielectric constant. The outer membranes of sperm mitochondria (10) have high concentration of selenium to protect against free radical damage. I suspect there is a lot more to learn about the role of the outer membrane.
References;
1. Age Related Changes in Rat Liver Mitochondria. pp182-188 John Spencer Thesis Birmingham University 1980.
2. Subcellular changes and apoptosis induced by ethanol in rat liver
4 BARJA, G. (1998), Mitochondrial Free Radical Production and Aging in Mammals and Birds. Annals of the New York Academy of Sciences, 854: 224–238. doi: 10.1111/j.1749-6632.1998.tb09905.x
5 : DECLINE IN RESPIRATORY CONTROL RATIO OF RAT-LIVER MITOCHONDRIA IN OLD-AGE
Author(s): HORTON, AA; SPENCER, JA Source: MECHANISMS OF AGEING AND DEVELOPMENT Volume: 17 Issue: 3 Pages: 253-259 DOI: 10.1016/0047-6374(81)90062-2 Published: 1981
