Abstract
Lysosomal cathepsins have recently been reported to play crucial roles in the regulation of the mitochondrial death cascade by an unclear mechanism leading to mitochondrial membrane permeabilization. Glycosaminoglycans (GAG) are a family of ionic polysaccharides present at the lysosomal compartment and shown to inhibit lysosomal cathepsin activities. The implication of this family of polysaccharides in the regulation of the pre-mitochondrial death cascade has still not been considered. Here, we demonstrate in a model of skin fibroblasts submitted to oxidative stress that a GAG–mimetic protects the lysosome from membrane disruption, reduces intracellular ROS levels, and inhibits mitochondrial membrane potential collapse, cytochrome c release and caspases-9 and -3 activations without affecting the extrinsic pathway of apoptosis. Heparan sulfate and chondroitin sulfate, but not heparin, showed also protecting effects when assessing key points of the intrinsic pathway of apoptosis. We suggest the existence of molecular links between endogenous GAGs and the regulation of apoptosis.
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Abbreviations
- GAGs:
-
glycosaminoglycans
- HS:
-
heparan sulfate
- CS:
-
chondroitin sulfate
- HEP:
-
heparin
- ROS:
-
reactive oxygen species
- H2O2:
-
hydrogen peroxide
- Δψm:
-
mitochondrial membrane potential
- RGTA:
-
regenerating agent
- HBP:
-
heparin-binding proteins
- MDA:
-
malondialdehyde
- AO:
-
acridine orange
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Acknowledgements
We thank Dr. Pierre Rustin (INSERM U676, Robert Debré, Paris France) for his helpful discussion.
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Yue, XL., Lehri, S., Li, P. et al. Insights on a new path of pre-mitochondrial apoptosis regulation by a glycosaminoglycan mimetic. Cell Death Differ 16, 770–781 (2009). https://doi.org/10.1038/cdd.2009.9
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DOI: https://doi.org/10.1038/cdd.2009.9
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