> This paper is doubly interesting to me, because theere is a paper in the new
> PNAS by Dawson and others, which shows that endogeneous, neural NO is
> suffiecient to combine with oxygen radicals from disturbed mitochondria, to
> generate peroxynitrite in quantities that can lead to Parkinsons Disease.
> This seems to provide experimental evidence suggesting that mildly
> dysfunctional mitochondria, peerhaps in conjunction with over-stimulated
> macrophages may make sufficient peroxynitrite in a chronic manner to
> seriously contribute to ageing in a variety of tissues. (This idea was
> originally formulated by Paolo Giacomoni)
>>> ---------- Forwarded message ----------
> Date: 18 May 1999 16:38:10 -0700
> From: "Paul S. Brookes." <brookes at uab.edu>
> To: ageing at hgmp.mrc.ac.uk> Subject: Mitochondrial deficiencies - any thoughts Aubrey?
>> 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
>> 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?
> 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
-- Dr. Sydney SHALL
CNRS, UPR 9003, Cancerogenese et Mutagenese Moleculaire et Structurale,
Ecole Superieure de Biotechnologie de Strasbourg, Boulevard Sebastien Brant
F-67400 Illkirch, France
TEL :00 33 3 88 65 53 69 ;FAX :00 33 3 88 65 53 43 ;
E-Mail: sydney.shall at esbs.u-strasbg.fr
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