higher ploidy and mitochondrial maintenance hypothesis
clejan at mindspring.com
Mon Aug 13 13:16:41 EST 2001
Incisive, merciless comments appreciated on the following.
Ploidy and mitochondrial maintenance hypothesis in hepatocytes:
Binucleation and resulting increase in ploidy is an adaptation which
benefits mitochondria and the cells they inhabit, allowing greater
expression of Mn SOD
and/or other antioxidants or proreplicants. I think that the key step in
achieving higher ploidy is binucleation through acytokinesis (Carriere
1969), and when growth is required as in PH (partial hepatectomy) or
response to thyroid hormone, cellular ploidy (not nuclear ploidy) is not
increased (I need to check this carefully). These are facts/ideas which
may support this hypothesis:
1. Despite greater size, higher ploidy hepatocytes have less mtDNA than
diploids (Loud 1968). More nDNA/mtDNA possibly means more proteins
involved in mito maintenace per mito, and more immunity to nDNA damage
for nDNA involved in mito maintanance (as well as other nDNA).
2. P450s and their resulting ROS are more highly expressed in
tetraploids (Gebhardt 1992) (more precisely in perivenular hepatocytes,
which are supposed to have a higher fraction of tetraploids than
periportal hepatocytes-Reid, private communication). Those cells that do
not protect their mitos sufficiently from the resulting oxidative
damage, by e.g. becoming binucleated and producing more anti-oxidants
targeted to mitochondria, perish.
3. Peroxisome proliferators increase ploidy. Possibly because of
increased ROS due to increased concentration of oxidases (Lalwani, 1997)
4. Transgenic mice with extra copies of Cu-Zn SOD have lower ploidy
(Nakatani, 1997) (it may be found in intermembrane space in mitos and
reduce the advantage of higher ploidy, while not incurring the penalties
of higher ploidy, whatever they may be (e.g. reduced replicative
5. Glutamine-Synthetase is more highly expressed in tetraploids. These
more highly differentiated cells are better able to cope with ammonia
elimination due to the higher expression of glutamine synthetase.
Production of urea in mitochondria from ammonia cannot occur unless
these are maintained in good shape. (Gebhardt, 1992)
6. Birds, fish, low metabolism rodents and herbivore primates, which
either do not produce much urea or produce uric acid or ammonia directly
do not have much binucleation and higher ploidy (Gahan, 1981, and
Cullen, 1994). There is not much ammonia to eliminate in these species
and hence not much advantage to either large GS production or increased
protection of mitos where GS production can occur.
7. Ploidy increases with age (Schmucker 1990) and faster with some
premature aging diseases (Gahan, 1984) . I have to examine this data
carefully to rule out the possibility that the increased nuclear ploidy
is due solely to binucleated cells replicating normally, increasing
nuclear but not cellular ploidy. If this is ruled out and the increased
ploidy is due to increased binucleation, then maybe increased ploidy is
an adaptive response to increased mitochondrial damage with age.
Facts which at first glance disagree with MMH:
1. Diploids survive better liver reperfusion after ischemia.
I would like to look at Wallace's SOD-/+ mice hepatocytes and see if
there is higher ploidy relative to WT. I also have a whole bunch of
proposed experiments, but first I want to rule out any of these ideas
based on known facts alone.
More information about the Ageing