Mitochondria and their host.
A relationship still in the making.
This article follows the previous post on the regulation of mitochondrial division by their ancestral ‘host’ cell. In this post I put forward the idea that in the post-mitotic somatic cell, mitochondrial proliferation must be inhibited (and must have always been inhibited) in order to prevent mitochondria from behaving like a bacterial infection rather than, as now, the essential symbiont in the aerobic eukaryote cell. The price for such suppression, I speculated, is senescence and cell death an idea I developed from my own work on regenerated liver mitochondria from senescent rats.1
In this post I wish to explore further the relationship between mitochondria and their host. After half a billion years of coexistence we consider mitochondria to be fully integrated with the ancestral host. It is clear that so much of their construction has been handed over to nuclear DNA and little remains to the mitochondrial DNA. However, even though much evolutionary time has elapsed I increasingly see the endosymbiotic relationship as a ‘work still in progress’.
To see the work in progress look for where the ‘joins’ are. That is to say, the junctures where the host’s biochemistry joins with that of the mitochondrion. Below are three areas where ‘the join shows’.
Getting Fat
The junction between glycolysis (the ancestral fermentation route for the production of chemical free energy) and the oxidative metabolism of the mitochondria is an obvious junction. Here, essentially, the products of glycolysis (fermentation) are taken to be fully oxidised by mitochondria thereby increasing the amount of energy available to the organism by an order of magnitude.
Essentially this is a hand-over process: simple sugars such as glucose and fructose absorbed directly from the diet into the bloodstream are taken up by cells or stored stored in the muscles and liver as glycogen. These sugars enter the glycolysis pathway mentioned above and are swiftly converted to what is essentially ‘mitochondrial fuel’.
A good supply of fuel is all well and good but what if there is a glut? Maybe the cell does not need much energy at this time and as a result the mitochondria are not accepting any more ‘fuel’. This is a bottle-neck and can only be safely resolved by shunting off the accumulating fuels into an inert store. Fortunately Nature has provided a fix and this is exactly what happens...we know this store as fat.
In short here we see evolution acting in typical kludge mode, stitching together two disparate systems and creating a ‘work around’ for some of the consequences. There is still a problem though. In the post mitotic cell mitochondria are obliged to age. This means that the sugar-produced (glycolysis/fermentation is sugar based) bottle-neck becomes inevitable.
Indeed as we humans age one very well reported change is our tendency to get fatter. Few, over 25 years old, trying to control their weight will have failed to notice that carbohydrate-rich foods seem to have a disproportionate ability to fatten us up.
Something is not quite going well with traffic flow at the junction! I think this is a good example to start with to illustrate the evolution of a working relationship between two biochemistries. A second example shows ( to my viewpoint) that the ancestral cell nearly abandoning the energetic payload of their guests.
Cancer
There has always been a paradox at the heart of rapidly growing tumours and that is the apparent contradiction between rapid cell division and growth and the paucity of mitochondria found in tumour tissue. Division and growth require energy and conventional wisdom has it that the explosion of multicellular life was down to the ‘new’ eukaryote cell with its abundance of energy resulting from its symbiosis with mitochondria.
Recent work on the cell’s energy economy suggests that the cost of building new mitochondria, (which would by the way involve unleashing mitochondrial division) is simply not worth the ‘expense’ as the basic cell, unburdened of the high energy needs of a liver, a brain or a muscle, can rely quite nicely on anaerobic metabolism alone. 2
Indeed I found that mitochondria from rapidly growing tumours produced in aged mice were indeed few in number but in all other respects identical to those found in young rats, so it’s not that the tumour cannot build good mitochondria they simply choose not to build that many of them. However they do have mitochondria and they do use their cytoskeleton to gather and to wrap these around the nuclei as would be the case in normal cells prior to mitosis..3
I think this part of the relationship between the cell ‘host’ and the mitochondrion is the key to multicellular development half a billion years ago. In a previous post with material taken from my thesis I developed a capacitance model for mitochondrial energy storage. During mitosis a cell cannot feed, yet a complex nucleus would require a lot of energy to divide. I think energy this is stored electrochemically in the capacitance of the mitochondria surrounding the nucleus.
In other words, the true utility value of the mitochondria to the cell is to power cell division. The specialised high energy functions used by differentiated tissues such as nerves and muscles came later. Below is my final example. Here I see mitochondria drawing a line in the sand with regard to their function. In this case the composition of their inner mebranes and from this their electrical integrity and ability to produce energyt through oxidation.
Cholesterol
Cholesterol is essential to mitochondrial function. The inner membrane of mitochondria is electrochemically speaking precisely engineered, It’s ionic permeability and dielectric properties are essential to its function. The level of cholesterol in the membrane is highly conserved, that is it is kept at a certain level come what may. In my work feeding rats very high levels of cholesterol produced an expected increase in cholesterol in all cellular structures which normally contained some cholesterol… but not though the mitochondrial inner membrane: it remained unmoved. So did the respiratory functions of the mitochondria which did not change with excess cholesterol in the cell..4
The converse experiment is very hard to do. Producing a cholesterol deficit is difficult as most animals including ourselves and the rat can produce cholesterol in the liver without a dietary source. Today this can be achieved easily using the drugs known as statins. These block cholesterol synthesis so on a low cholesterol diet a deficit can be easily produced. I can find little work on cholesterol deprivation on mitochondrial function but it has been shown that simvastatin reduces mitochondrial function in yeast. It may be that many of the reported side effects in aged humans on low cholesterol diets whilst on statin drugs may be due to adverse effects on already struggling mitochondria. 5
The bad side of cholesterol, that is arterial disease, may be a nasty side effect of the absolute requirement to meet the cholesterol needs of the energy producers, the mitochondria. This would be critical in tissues like the brain and muscles which rely heavily on a high energy economy.
To conclude, I think there is profit in looking at the relationship between mitochondria and their hosts. Compromises of co-existence honed and developed by the pressures of evolution will be everywhere the two biochemistries meet. I think I have highlighted just three.
- REVERSAL OF AGE-DEPENDENT DECLINE IN RESPIRATORY CONTROL RATIO BY HEPATIC REGENERATION HORTON, AA; SPENCER, JA FEBS LETTERS Volume: 133 Issue: 1 Pages: 139-141 DOI: 10.1016/0014-5793(81)80490-5 Published: 1981 Times Cited: 4 (from Web of Science)
2) Overflow metabolism in Escherichia coli results from efficient proteome allocation:
Markus Basan, Sheng Hui,Hiroyuki Okano, Zhongge Zhang, Yang Shen, James R. Williamson& Terence Hwa
Nature 528,99–104(03 December 2015) doi:10.1038/nature15765
‘Using experimental proteomics and modelling in E. coli, the amount of protein needed to run respiration (per ATP produced) is shown to be twice as much as that needed to run fermentation’
3) Biochimica et Biophysica Acta (BBA) - BioenergeticsThe relationship between mitochondrial shape and function and the cytoskeleton Vasiliki Anesti, Luca Scorrano, Dulbecco-Telethon Institute, Venetian Institute of Molecular Medicine, Via Orus 2, I-35129, Padova, Italy Received 13 January 2006, Revised 13 March 2006, Accepted 7 April 2006, Available online 19 April 2006
4) The Cholesterol Content of Mitochondria from Mature and Old Rats P151-160
Age-related changes in Rat Liver Mitochondria J A Spencer Ph.D thesis 1980 Birmingham University, unpublished work.
5) Simvastatin reduces ergosterol levels, inhibits growth and causes loss of mtDNA inCandida glabrata Christiane Westermeyer & Ian G. Macreadie CSIRO
Health and Molecular and Technologies and P-Health Flagship, Parkville, Victoria, Australia
All publications by J Spencer:
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Author(s): HORTON, AA; SPENCER, JA
Source: FEBS LETTERS Volume: 133 Issue: 1 Pages: 139-141 DOI: 10.1016/0014-5793(81)80490-5 Published: 1981
Times Cited: 4 (from Web of Science)
Author(s): Spencer, John A.; Horton, Alan A.
Source: BIOCHEMICAL SOCIETY TRANSACTIONS Volume: 7 Pages: 1260-1262 DOI: 10.1042/bst0071260 Part: 6 Published: DEC 1979
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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
Author(s): Spencer, John A.; Horton, Alan A.
Source: BIOCHEMICAL SOCIETY TRANSACTIONS Volume: 7 Pages: 673-675 DOI: 10.1042/bst0070673 Part: 4 Published:AUG 1979
Times Cited: 0 (from Web of Science)
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Author(s): SPENCER, JA; HORTON, AA
Source: EXPERIMENTAL GERONTOLOGY Volume: 13 Issue: 3-4 Pages: 227-& DOI: 10.1016/0531-5565(78)90016-5 Published: 1978
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The simultaneous oxidation of substrates by rat liver mitochondria [proceedings].
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