Doug Wallace has just published a very interesting paper (PNAS 96,
4820-4825) in which they show that mice deficient in the heart/muscle
isoform of the adenine nucleotide translocase (ANT) exhibit higher levels
of oxidative stress. They show that this is due to increased mitochondrial
production of H2O2. SOD and other antioxidant enzymes are up-regulated in
response.
Here's my alternative explanation....
The ANT is an essential component of the permeability transition pore
(Andrew Halestrap's work). Therefore without the ANT, pore operation is
affected, so mitochondrial Ca2+ homeostasis will be upset. If one believes
that pore opening and subsequent cytochrome c release are essential
components of the apoptotic cascade, then these cells will have an impaired
apoptotic ability. This means the tissue will not be able to dispose of
cells that contain "high ROS producing" mitochondria, a la Aubrey's theory
on mito's and cell death.
In addition it could explain their observation that ROS production by the
mitochondria in vitro is higher - the tissue gradually accumulates a
population of ROS producing mitochondria that it has no way of getting rid
of. This is the only way I can see that loss of the ANT would cause
increased ROS production by mito's, as ANT does not have a lot of control
over ox-phos, so knocking it out doesn't necessarily affect respiratory (or
ROS producing) activity that much.
I am of course assuming that pore opening and cyt-c release are essential
events in apoptosis, which of course may not be the case, depending on
which papers you read and what cell type it was done in, and whether it was
a transformed cell line or primary culture - but hey, thats another
minefield which I'd rather not get into!
Comments please?
Paul
______________________________________________
Dr. Paul S. Brookes. (brookes at uab.edu)
UAB Department of Pathology, G004 Volker Hall
1670 University Blvd., Birmingham AL 35294 USA
Tel (001) 205 934 1915 Fax (001) 205 934 1775
http://peir.path.uab.edu/brookes
