TNF?-induced lysosomal membrane permeability (LMP) is downstream of MOMP and triggered by caspase-mediated p75 cleavage and ROS formation
20.06.2013
Huai J, Vögtle FN, Jöckel L, Li Y, Kiefer T, Ricci JE, Borner C.
J Cell Sci. 2013;126(Pt 17):4015-25
Here we show that in contrary to previous belief, TNF alpha does not directly induce lysosomal membrane permeability (LMP), but first activates Bax/Bak, leading to cytochrome c release, apoptosome formation and caspase-3 activation. Caspase-3 then feeds back on complex I of the mitochondrial respiratory chain and cleaves its component p75 NDUFS1. This provokes the generation of O2?. (ROS) which is converted into H2O2 generating . OH in lysosomes via the Fenton reaction. The resulting LMP releases cathepsin B and L, which further amplify apoptosis via Bid cleavage and caspase-3 activation.
