Aging, Mitochondrial proliferation and epigenetics
Mitochondria represent a huge metabolic resource for the eukaryotic cell due to the simple fact they confer a huge ten-fold ‘turbo-boost’ to the low-energy fermentation-like respiration indigenous to the archaic cell.
Mitochondria came to live within their host organism probably 2 billion years ago. However, even though now largely tamed by their host, their complexity and atavistic ability to divide and reproduce mean that this boost comes with a risk and a cost.
In rapidly reproducing cancer cells for example, mitochondria are largely ditched in favour of the old fermenting ways, simply because a ‘quick and dirty’ replication of the whole cell without making and supporting a whole load of mitochondria carries a lower energetic cost than would the fully functioning mitochondria-rich model. Cancer cells must know how to suppress mitochondrial replication.
Mitochondrial replication and proliferation within a cell must have been a real headache in the earliest days as in effect the ‘visitor’ was a bacterium swimming in a soup of intracellular nutrients ... perfect for reproduction. Parasitic bacterium to symbiotic mitochondrion is a big step. Early on and relatively simply, the host cell must have had the ability to control the mitochondrion’s rate of division and most probably this would have involved a widely used pathogen defence mechanism.
In the present day postmitotic somatic cell, I think this control is basically set to ‘on’ and moreover therein lays the key to the aging mitochondrion and in turn the aging cell. The intense free radical-rich environment generated by mitochondria results in (well documented) damage and the ‘repair bills’ for this activity most likely mount up over time ... but without the ‘start-over’ option invoked by replication the mitochondria will senesce. They enlarge and eventually trigger apoptosis as they start to leak.
In a paper taken from my thesis, livers from very old rats in senescence were induced to regenerate following partial hepatectomy. To cut a long story short the ‘new’ tissue hosted mitochondria that were indistinguishable from those found in young rats as well as fewer ‘legacy’ mitochondria morphologically similar to those from older rats. The conclusion was that dividing mitochondria are built ‘as new’ from undamaged blueprints, even in senescent cells.
What follows is speculation. What can be a the simple mechanism for controlling mitochondrial division be? My candidates are the histone proteins. They are present in the ancient bacteria the archaea which can carry out phagocytosis. That is they can ingest smaller organisms in the manner the putative ancestral eukaryote did with mitochondria. Histones are toxic to mitochondria and can bind to them and kill them. Histones also accumulate in liposomes ( fatty droplets within the cell) and can be used to kill invasive bacteria in some eukaryotic tissues.
Histones ( and there are a great many to choose from) therefore could form the basis of a regulatory system to prevent mitochondria from uncontrolled proliferation in the post mitotic cell.
If so, then this begs the question whether there is any epigenetic route to change this control. Maybe to allow a bit more mitochondrial proliferation and thus to rejuvenate a cell. In my thesis two populations of mitochondria were always present in rat liver preparations, the ……… increasing with age and decreasing with hepatic regeneration. So far the B and D vitamins seem the most promising having both been shown to modify histone acetylases and methylations. As is well known Vitamin D deficiency is linked with age-related dementia and B12 along with B6 and B5 to many of age - related ailments
As stated previously this is speculation but the possibility of an epigenetic back door into mitochondrial well being is deeply attractive.
