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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 …