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Free Radic Biol Med. 2013 Dec;65:26-37. doi: 10.1016/j.freeradbiomed.2013.05.051. Epub 2013 Jun 14.

Noxa couples lysosomal membrane permeabilization and apoptosis during oxidative stress.

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1
Molecular Targets Program, James Graham Brown Cancer Center, Departments of Medicine, Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, USA.

Abstract

The exact roles of lysosomal membrane permeabilization (LMP) in oxidative stress-triggered apoptosis are not completely understood. Here, we first studied the temporal relation between LMP and mitochondrial outer membrane permeabilization (MOMP) during the initial stage of apoptosis caused by the oxidative stress inducer H2O2. Despite its essential role in mediating apoptosis, the expression of the BH3-only Bcl-2 protein Noxa was dispensable for LMP. In contrast, MOMP was dependent on Noxa expression and occurred downstream of LMP. When lysosomal membranes were stabilized by the iron-chelating agent desferrioxamine, H2O2-induced increase in DNA damage, Noxa expression, and subsequent apoptosis were abolished by the inhibition of LMP. Importantly, LMP-induced Noxa expression increase was mediated by p53 and seems to be a unique feature of apoptosis caused by oxidative stress. Finally, exogenous iron loading recapitulated the effects of H2O2 on the expression of BH3-only Bcl-2 proteins. Overall, these data reveal a Noxa-mediated signaling pathway that couples LMP with MOMP and ultimate apoptosis during oxidative stress.

KEYWORDS:

AO; Apoptosis; Bcl-2 proteins; DFO; H(2)O(2); Iron; LMP; Lysosomes; MEFs; MOMP; Oxidative stress; acridine orange; desferrioxamine; hydrogen peroxide; lysosomal membrane permeabilization; mitochondrial outer membrane permeabilization; mouse embryonic fibroblasts

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