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[A1CR]

posted on behalf of CRON4healthyfuture 2006-03-26:

PNAS: Primary role of mitochondria in vascular endothelium, NOT ATP!!

It's not the ATP, STUPID.

It's the SIGNAL! ["What's the frequency?"]

The future is now!

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"......the primary role of mitochondria in vascular endothelial cells may not be to generate ATP but, under the control of NO, to act as signaling organelles using either O2 or O2-derived species as signaling molecules."

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"We have confirmed that oxidative phosphorylation is not the main source of ATP generation in these cells. We also show that at a low O2 concentration (<1%) endogenous NO plays a key role in preventing the accumulation of the -subunit of hypoxia-inducible factor 1. At higher O2 concentrations (1-3%) NO facilitates the production of mitochondrial reactive oxygen species. This production activates the AMP-activated protein kinase by a mechanism independent of nucleotide concentrations. Thus, the primary role of mitochondria in vascular endothelial cells may not be to generate ATP but, under the control of NO, to act as signaling organelles using either O2 or O2-derived species as signaling molecules. "

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http://www.pnas.org/cgi/content/abstract/0601026103v1

[MR]

CRON4healthyfuture wrote:
> It's not the ATP, STUPID.
>
> It's the SIGNAL! ["What's the frequency?"]

The tone of your statement here suggests frustration with a legioin of
"STUPID" folks claiaming that "it" (aging? Hypertension?) *is* the ATP.
Certainly, there are advocates of various "mitochondrial free radical
theories of aging" that posit an age-related decline in cellular ATP
availability due to widespread mitochondrial decay, typically taken to
involve a "vicious cycle" of increasing mtROS generation and decreased
ATP production, starving the cell of energy and leading to a downward
spiral of bioenergetic decay. These ideas continue to have their
prominent advocates, and are widely presumed to constitute "the"
"mitochondrial free radical theories of aging" -- despite the fact that
it's been pretty hard to show that such a decay actually happens to any
physiologically significant degree on any widespread scale in aging, or
that CR (which retards aging) has any effect on same.

I think that I should point out, however (as I've done several times in
the past few years in discussion of these subjects with you (PCRON4healthyfuture):

[check the Archives at the CRSociety]

... Aubrey de Grey's *specific* MiFRA theory (1-4) does not posit a
bioenergetic decline, except in a tiny fraction (<1%) of postmitotic
cells, where it is not a slow decay but a sudden shutdown -- and where
the ATP deficit as such is not the mechanism whereby mitochondrial
damage accelerates aging.

Also, of course, the same theory is about postmitotic cells -- not
mitotic ones like those of the endothelia.

Altogether separate from this, it's quite interesting that there is so
completely different an ATP source in these cells.

-MR


0. Quintero M, Colombo SL, Godfrey A, Moncada S.
Mitochondria as signaling organelles in the vascular endothelium.
Proc Natl Acad Sci U S A. 2006 Mar 24; [Epub ahead of print]
PMID: 16565215 [PubMed - as supplied by publisher]
http://www.pnas.org/cgi/content/abstract/0601026103v1

1. de Grey AD. The reductive hotspot hypothesis of mammalian aging:
membrane metabolism magnifies mutant mitochondrial mischief. Eur J
Biochem. 2002 Apr;269(8):2003-9. Review. PMID: 11985576 [PubMed -
indexed for MEDLINE]
http://www.gen.cam.ac.uk/sens/mmmmmm.pdf

2. de Grey AD. The mitochondrial free radical theory of aging. 1999;
Austin, TX: Landes Bioscience. (ISBN 1-57059-564-X).

3. de Grey AD. A proposed refinement of the mitochondrial free radical
theory of aging. Bioessays. 1997 Feb;19(2):161-6. Review. PMID: 9046246
[PubMed - indexed for MEDLINE]
http://www.gen.cam.ac.uk/sens/manu7.pdf

4. de Grey ADNJ. A mechanism proposed to explain the rise in oxidative
stress during aging. J Anti-Aging Med 1998; 1(1):53-66.
http://www.gen.cam.ac.uk/sens/pmor.pdf