Persistent mitochondrial dysfunction and oxidative stress hinder neuronal cell recovery from reversible proteasome inhibition

Apoptosis : an International Journal on Programmed Cell Death
Luena Papa, Patricia Rockwell

Abstract

Oxidative stress, proteasome impairment and mitochondrial dysfunction are implicated as contributors to ageing and neurodegeneration. Using mouse neuronal cells, we showed previously that the reversible proteasome inhibitor, [N-benzyloxycarbonyl-Ile-Glu (O-t-bytul)-Ala-leucinal; (PSI)] induced excessive reactive oxygen species (ROS) that mediated mitochondrial damage and a caspase-independent cell death. Herein, we examined whether this insult persists in neuronal cells recovering from inhibitor removal over time. Recovery from proteasome inhibition showed a time and dose-dependent cell death that was accompanied by ROS overproduction, caspase activation and mitochondrial membrane permeabilization with the subcellular relocalizations of the proapoptotic proteins, Bax, cytochrome c and the apoptosis inducing factor (AIF). Caspase inhibition failed to promote survival indicating that cell death was caspase-independent. Treatments with the antioxidant N-acetyl-cysteine (NAC) were needed to promote survival in cell recovering from mild proteasome inhibition while overexpression of the antiapoptotic protein Bcl-xL together with NAC attenuated cell death during recovery from potent inhibition. Whereas inhibitor removal increased prot...Continue Reading

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Citations

Feb 6, 2010·Proceedings of the National Academy of Sciences of the United States of America·Kojiro TakedaMitsuhiro Yanagida
Mar 6, 2010·Annals of the New York Academy of Sciences·Bryan K YamamotoGary A Gudelsky
Dec 3, 2014·Neuroscience Letters·V A CarozziA Chiorazzi
Sep 16, 2008·Biochimica Et Biophysica Acta·Brandi R WhatleyLih-Shen Chin
Apr 18, 2009·Molecular Aspects of Medicine·Tobias JungTilman Grune
Jun 7, 2017·Molecular Neurobiology·Vivian Strassburger AndradeClovis Milton Duval Wannmacher

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