Cancer cell division and leaky mitochondria: a trigger?

Recently, reading a fascinating paper from a young researcher on the suppression of mitochondrial activity (both respiration and division)  in cancer tumours.1, That cancer cells largely rely on sugar and the anaerobic pathway called glycolysis alone to produce energy, rather than oxidative phosphorylation, was well known, but the mechanism of suppression of mitochondria and the therapeutic possibility of reversal was unknown to me.

 In my own work so many years ago we induced tumours in old and young rats and isolated the mitochondria in the conventional way. We found as others did that there were few mitochondria to be had and that there were no differences in the so called respiratory quotient (RC) between tumours from old and young rats.We concluded, wrongly I now think, that ‘no difference’ meant the tumour mitochondria had been ‘rejuvenated’ … even though their RCs were pretty average (3-4) in any case. More about this latter observation later.

 In any case, cell division in tumours does not need the energy provided by mitochondria.. Multicellular creatures are traditionally described as being able to emerge through evolutionary time due to the energy bounty provided by mitochondria; they need it to ‘fund’ a highly organised low entropy matrix of differentiated cells movement and nervous communication..

 Tumors are by definition multicellular but their internal organisation is minimal which due to the much lower thermodynamic pressures needed for low entropy states  presumably enables them to divide and grow on the low energy yields from glycolysis without the ability to differentiate, move and ‘think’.

 But why divide at all? There is no future after death, no chance of persistence over time, in other words no driver to run this show. Traditionally cancer cell division is studied in incredible depth for obvious reasons but at the ‘why?’ level there is a fall back to saying ‘rogue cells, out of control etc’.

 In previous blogs2 I have referred to the junction between the ancient glycolysis pathway of the cell’s cytoplasm and the TCA oxidative respiration cycle of the mitochondria. My suspicion always has been that it is a kludge. Its kludgy symbiont origins show as we age; we become less able to handle carbohydrates and get fat on them instead of burning them in mitochondria (which are essentially fat burners).

 I suspect that cell division in cancers is the echo of an atavistic response by unicellular anaerobes to ‘infection’ by mitochondria/bacteria. A two pronged response would be effective:

 1) inhibit mitochondrial division and
2) divide, by what is called binary fission in Amoeba but is really mitosis by definition for eukaryote cells.

 Imagine you have 10 invaders evenly distributed, two fissions and you have 2-3 in each, three divisions and it’s possible statistically that one cell is free of infection. Four divisions and this likelihood increases. I will never forget first seeing mitochondria using light microscopy whizzing through the cytoskeleton as if on a  complex motorway system. Selective cytokinesis could enhance the effectiveness of a division strategy by streaming and compartmentalising invading bacteria.

 But I can’t yet find evidence for stimulation of cell division in anaerobes or even single celled organisms such as protist. by ‘intruders’ there is some ‘old but good’3 stuff on the intruders such as bacteria as they evade the lysosomes. Outcomes range from relationships with intruders form obligate symbiont to outright killers. Lots on the response of bacteria to phagocyte predation ( for obvious reasons since that’s what our killer white blood cells do to bacteria) but on the ‘host’ cell’s response … nothing. So I am on my own here. A host response is pure speculation.

 However, there’s more speculation to follow.

 When I used to prepare mitochondrial isolates from the livers of old and young rats it took a long time get to the point where the mitochondria showed good respiratory control ratios (RC) indicating that they were in good shape. Typically ratios 4-5 would be ‘good’. I found small age related difference between old and young preparations ( old had lower RCs) as expected. However sometimes I prepared mitochondria from young animals that had ratios 10 and more. This never lasted for half an hour and never did I get this from old preparations.

My feeling today is that we ended up comparing young damaged mitos with old slightly more damaged mitos and the reason was leakage of Cytochrome C which I already knew was happening in older mitochondria4.

 So consider this; from the host cells point of view, are mitochondria friends or foes? I think that the relationship between glycolysis ( host cell) and oxidative respiration (symbiont visitor) becomes strained as we age. We know that mitochondria are cell killers. Their ability to destroy a cell (apoptosis) is used by the body to clear out zombie  or damaged cells. They do this with increasingly with age ruthlessly decommissioning under used muscle cells (sarcopena).They do so by releasing Cytochrome C setting off a cascade of reactions leading cell death!
We know also that mitochondrial division reduces with age and they enlarge to compensate5.

 So finally, in the aging cell do leaky mitochondria activate an atavistic defence response from the host cell leading to suppression of mitochondrial division and setting off unregulated ‘defence’ mitosis?


https://www.ncbi.nlm.nih.gov/pubmed/20849810

  G Solaini - ‎2011

 2)  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



3)Protozoa and Protists Michael A Sleigh Cambridge Press 1973: https://books.google.co.uk/books?id=K2Y4AAAAIAAJ&pg=PA281&lpg=PA281&dq=bacterial+infection+of+anaerobic+protists&source=bl&ots=BwLasl4cJs&sig=Zm4ozp8HKwa2SYOuTVaNfjZtLpU&hl=en&sa=X&ved=0ahUKEwiTitCAw9XZAhVUGsAKHV-bBfgQ6AEIUDAE#v=onepage&q=bacterial%20infection%20of%20anaerobic%20protists&f=false4

 4) Implication of mitochondria in apoptosis. Detection of Mitochondrial Diseases, Developments in Molecular and Cellular Biochemistry Volume 21, 1997, pp 185-188 Patrice Xavier Petit, Naoufal Zamzami, Jean-Luc Vayssière, Bernard Mignotte, Guido Kroemer, Maria Castedo
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) Release of Cytochrome C by osmotic swelling. J.A Spencer and Alan A Horton 1979