Nishikawa et al. Nature 404 p787

Paul S. Brookes. brookes at uab.edu
Mon Apr 17 14:59:00 EST 2000


Anyone seen this paper?

The basic thrust of the paper is that increased mitochondrial ROS 
production is responsible for many of the pathways of hyperglycaemic 
damage.  One interesting thing they propose is that the accumulation of 
advanced glycation end products (AGEs) is increased because the oxidative 
stress damages GAPDH and so glyceraldehyde-3-phosphate accumulates, leading 
to methylglyoxal and then AGEs.

Later on in the paper they say aldose reductase is reversibly inhibited by 
s-nitrosation, and that increased mt ROS would reduce the available NO, so 
the enzyme would not be so inhibited, and would lead to accumulation of 
sorbitol (another damage pathway).    But.... I was under the impression 
that GAPDH was inhibited by s-nitrosation too, so they're arguing opposite 
effects for 2 different proteins.

Questions....
1: How can this be?  Is GAPDH really inhibited by oxidative stress (I 
thought it was nitrosative).
2: Has anyone shown that increasing mt ROS by other means (e.g. antimycin A 
in cells) leads to changes in GAPDH activity.  Presumably anything that 
shuts off ox-phos will lead to increased glycolysis and an induction of 
GAPDH mRNA, which would counter any inhibitory effect of ROS.
3: Could this be an important mediator in the mito FR theory of ageing, 
i.e. ageing mito's make more ROS which inhibits GAPDH leading to AGE 
accumulation.  Has anyone examined AGEs in animals with differnet ageing 
rates and mito ROS rates to see if there's a correlation.

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

The quality of e-mails can go down as well as up
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