Induction of the Nrf2-driven Antioxidant Response Confers Neuroprotection during Mitochondrial Stress in Vivo

Shih, Andy Y.; Imbeault, Sophie; Barakauskas, Vilte; Erb, Heidi; Jiang, Lei; Li, Ping; Murphy, Timothy H.

doi:10.1074/jbc.m414635200

Cited by 242 publications

(205 citation statements)

References 74 publications

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“…To date there is no clear consensus about the effect of rotenone on mitochondrial ROS generation under various conditions; however, such contradictory reports support the need for further investigation into the intricacies of mechanisms of mitochondrial ROS generation and suppression. Recently, two studies demonstrated a protective function of Nrf2 in mitochondrial dysfunction and oxidative stress caused by the complex II inhibitor, 3-nitropropionic acid [37,38]. These findings, along with our results in this study suggest that ferritin H may be a target gene in the response to mitochondrial dysfunction and oxidative stress produced by rotenone insult.…”

Section: Discussionsupporting

confidence: 86%

Role and regulation of ferritin H in rotenone-mediated mitochondrial oxidative stress

Mackenzie

Ray

Tsuji

2008

Free Radical Biology and Medicine

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Tight regulation of intracellular iron levels in response to mitochondrial dysfunction is an important mechanism that prevents oxidative stress, thereby limiting cellular damage. Here, we describe a cytoprotective response involving transcriptional activation of the ferritin H gene in response to the mitochondrial complex I inhibitor and neurotoxic compound, rotenone. Rotenone exposure increased ferritin H mRNA and protein synthesis in NIH3T3 fibroblasts and SH-SY5Y neuroblastoma cells. Transient transfection of a ferritin H promoter-luciferase reporter into NIH3T3 cells showed that ferritin H was transcriptionally activated by rotenone through an antioxidant responsive element (ARE). Chromatin immunoprecipitation assays showed that rotenone treatment enhanced binding of Nrf2 and JunD transcription factors to the ARE. In addition, rotenone induced production of reactive oxygen species (ROS), and pretreatment with N-acetylcysteine abrogated ferritin H mRNA induction by rotenone, suggesting that this response is oxidative stress-mediated. Furthermore, reduced ferritin H expression by siRNA sensitized cells to rotenone-induced apoptosis with enhanced ROS production and annexin V positive cells. Taken together, these results suggest that ferritin H transcription is activated by rotenone via an oxidative stress-mediated pathway leading to ARE activation, and may be critically important to protect cells from mitochondrial dysfunction and oxidative stress.

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Section: Discussionsupporting

confidence: 86%

Role and regulation of ferritin H in rotenone-mediated mitochondrial oxidative stress

Mackenzie

Ray

Tsuji

2008

Free Radical Biology and Medicine

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“…Moreover, Nrf2 induces synthesis of a battery of enzymes that coordinate a protective response to oxidative stress via binding to the ARE promoter region, which is present in the xCT gene (Chanas et al,2002;Sasaki et al,2002;Shih et al,2005). Much of the previous research using Nrf2 KO has been conducted in cultured embryonic cells, and these studies clearly show that cells lacking Nrf2 are deficient in the induction of phase 2 antioxidant enzymes by oxidative stressors (Ishii et al,2000;Kraft et al,2004;Lee et al,2003a;Lee et al,2003b).…”

Section: Discussionmentioning

confidence: 99%

“…Also, in primary neuronal or glial cultures the loss of Nrf2 reduces the constitutive and inducible expression of cytoprotective genes (Lee et al,2003a;Lee et al,2003b;Shih et al,2005), and Nrf2 over-expression in glia cells protects neurons from oxidative stress (Shih et al,2003). Finally, constitutive deletion of the Nrf2 gene in vivo reduces the induction of glutathione-dependent enzymes in the liver, and augments cortical and striatal lesions induced by the mitochondrial complex II inhibitor 3-nitropropionic acid (Calkins et al,2005;Chanas et al,2002;Shih et al,2005). Therefore, it has been concluded from in vitro and in vivo studies that Nrf2 controls the expression of xCT as part of a cellular response that protects cells against oxidative stress.…”

Section: Introductionmentioning

confidence: 99%

Nrf2 gene deletion fails to alter psychostimulant-induced behavior or neurotoxicity

et al. 2007

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The transcription factor NF-E2-related factor (Nrf2) regulates the induction of phase 2 detoxifying enzymes by oxidative stress, including synthesis of the catalytic subunit (xCT) of the heterodimeric cystine-glutamate exchanger (system xc-). Repeated cocaine treatment in rats causes persistent neuroadaptations in glutamate neurotransmission in the nucleus accumbens that result, in part, from reduced activity of system xc-. Since in vitro under-or over-expression of Nrf2 regulates system xcactivity and xCT content, it was hypothesized that in vivo deletion of the Nrf2 gene would: 1) decrease system xc-activity, 2) produce a behavioral phenotype resembling that elicited by chronic cocaine administration, and 3) enhance dopamine depletion after methamphetamine-induced oxidative stress. In all three experiments no genotypic difference was measured between mice sustaining homozygous Nrf2 gene deletion and wild-type littermates. Thus, while Nrf2 is a transcriptional regulator of xCT and capable of protecting cells from oxidative stress, following Nrf2 gene deletion this role can be partially compensated by other mechanisms and methamphetamine-induced oxidative stress and dopamine toxicity does not significantly involve Nrf2.

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“…For instance, Shih, et al [37] demonstrated that Nrf2 pathway activation by tert-butylhydroquinone resulted in decreased brain toxicity in WT, but not N0 mice, following to exposure to ROS generated during 3-nitroproprionic acid-induced mitochondrial uncoupling. Also, tert-butylhydroperoxide-induced oxidative stress was repressed by triterpenoid activation of Nrf2 signaling in WT, but not N0 MEF cells [38].…”

Section: Discussionmentioning

confidence: 99%

Nrf2 regulates an adaptive response protecting against oxidative damage following diquat-mediated formation of superoxide anion

Osburn

Wakabayashi

Misra

et al. 2006

Archives of Biochemistry and Biophysics

175

135

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Mouse embryonic fibroblasts derived from Nrf2 −/− mice (N0) and Nrf2 +/+ mice (WT) have been used to characterize both basal and diquat (DQ)-induced oxidative stress levels and to examine Nrf2 activation during exposure to DQ-generated superoxide anion. Microarray analysis revealed that N0 cells have similar constitutive mRNA expression of genes responsible for the direct metabolism of reactive oxygen species but decreased expression of genes responsible for the production of reducing equivalents, repair of oxidized proteins and defense against lipid peroxidation, compared to WT cells. Nonetheless, the basal levels of ROS flux and oxidative damage biomarkers in WT and N0 cells were not different. Diquat dibromide (DQ), a non-electrophilic redox cycling bipyridylium herbicide, was used to generate intracellular superoxide anion. Isolated mitochondria from both cell lines exposed to DQ produced equivalent amounts of ROS, indicating a similar cellular capacity to generate ROS. However, N0 cells exposed to DQ for 24-hr exhibited markedly decreased cell viability and aconitase activity as well as increased lipid peroxidation and glutathione oxidation, relative to WT cells. 2′,7′-Dichlorofluorescein fluorescence was not increased in WT and N0 cells after 30-min of DQ exposure. However, increased levels of ROS were detected in N0 cells but not WT cells after 13-hr of DQ treatment. Additionally, total glutathione concentrations increased in WT, but not N0 cells following a 24-hr exposure to DQ. DQ exposure resulted in activation of an antioxidant response elementluciferase reporter gene, as well as induction of Nrf2-regulated genes in WT, but not N0 cells. Thus the enhanced sensitivity of N0 cells does not reflect basal differences in antioxidative capacity, but rather an impaired ability to mount an adaptive response to sustained oxidative stress.

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Induction of the Nrf2-driven Antioxidant Response Confers Neuroprotection during Mitochondrial Stress in Vivo

Cited by 242 publications

References 74 publications

Role and regulation of ferritin H in rotenone-mediated mitochondrial oxidative stress

Role and regulation of ferritin H in rotenone-mediated mitochondrial oxidative stress

Nrf2 gene deletion fails to alter psychostimulant-induced behavior or neurotoxicity

Nrf2 regulates an adaptive response protecting against oxidative damage following diquat-mediated formation of superoxide anion

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