Pathological apoptosis by xanthurenic acid, a tryptophan metabolite: activation of cell caspases but not cytoskeleton breakdown.
BACKGROUND
A family of aspartate-specific cysteinyl proteases, named caspases, mediates programmed cell death, apoptosis. In this function, caspases are important for physiological processes such as development and maintenance of organ homeostasis. Caspases are, however, also engaged in aging and disease development. The factors inducing age-related caspase activation are not known. Xanthurenic acid, a product of tryptophan degradation, is present in blood and urine, and accumulates in organs with aging.


RESULTS
Here, we report triggering of apoptotic key events by xanthurenic acid in vascular smooth muscle and retinal pigment epithelium cells. Upon exposure of these cells to xanthurenic acid a degradation of ICAD/DFF45, poly(ADP-ribose) polymerase, and gelsolin was observed, giving a pattern of protein cleavage characteristic for caspase-3 activity. Active caspase-3, -8 and caspase-9 were detected by Western blot analysis and immunofluorescence. In the presence of xanthurenic acid the amino-terminal fragment of gelsolin bound to the cytoskeleton, but did not lead to the usually observed cytoskeleton breakdown. Xanthurenic acid also caused mitochondrial migration, cytochrome C release, and destruction of mitochondria and nuclei.


CONCLUSIONS
These results indicate that xanthurenic acid is a previously not recognized endogenous cell death factor. Its accumulation in cells may lead to accelerated caspase activation related to aging and disease development.
Malina
H Z
HZ
Swiss Cardiovascular Research Center, Inselspital, CH-3010 Bern, Switzerland. hmalina@hotmail.com
Richter
C
C
Mehl
M
M
Hess
O M
OM
D017209:Apoptosis; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D003599:Cytoskeleton / Q000187:drug effects / Q000648:ultrastructure; D004789:Enzyme Activation; D006801:Humans; D008875:Middle Aged; D008928:Mitochondria / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology / Q000648:ultrastructure; D014364:Tryptophan / Q000378:metabolism; D014977:Xanthurenates / Q000378:metabolism / Q000633:toxicity*
D014977:Xanthurenates; C028330:xanthurenic acid; D014364:Tryptophan; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases