Cyanide Enhancement of Dopamine-Induced Apoptosis in Mesencephalic Cells Involves Mitochondrial Dysfunction and Oxidative Stress

Jones, Douglas C.; Prabhakaran, Krishnan; Li, Li; Gunasekar, Palur G.; Shou, Yan; Borowitz, Joseph L.; Isom, Gary E.

doi:10.1016/s0161-813x(03)00042-1

Cited by 41 publications

(27 citation statements)

References 40 publications

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“…The apoptotic cell death is initiated by mitochondrial dysfunction in which cytochrome c oxidase is inhibited and an increased ROS generation is produced [22]. The present study clarifies the underlying signaling cascade in a dopaminergic cell model and shows that cyanide activates the HIF pathway to upregulate BNIP3.…”

Section: Discussionsupporting

confidence: 53%

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HIF-1α activation by a redox-sensitive pathway mediates cyanide-induced BNIP3 upregulation and mitochondrial-dependent cell death

Zhang

Liu

et al. 2007

Free Radical Biology and Medicine

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Cyanide produces degeneration of the nervous system in which different modes of cell death are activated in the vulnerable brain areas. In brain, the mechanism underlying the cell death is not clear. In this study, an immortalized dopaminergic cell line was used to characterize the cell death signaling cascade activated by cyanide. Cyanide-treated cells exhibited a time-and concentration-dependent apoptosis that was caspase-independent. Cyanide induced a rapid surge of intracellular reactive oxygen species (ROS) generation, followed by p38 mitogen-activated protein kinase (MAPK) activation and nuclear accumulation of hypoxia-inducible factor-1α (HIF-1α). Activation of p38 MAPK and HIF-1α accumulation were attenuated by N-acetyl-L-cysteine (antioxidant), catalase (hydrogen peroxide scavenger) or a selective p38 MAPK inhibitor (SB203580). Cyanide activated the hypoxia response element (HRE) promoter, which was also blocked by the antioxidants and SB203580. HRE activation was followed by increased BNIP3 gene transcription, as reflected by elevated BNIP3 mRNA and protein levels. BNIP3 upregulation was reduced by selective RNAi knockdown of HIF-1α. Overexpression of BNIP3 produced mitochondrial dysfunction (reduced membrane potential), caspase-independent apoptosis, and sensitization of the cells to cyanideinduced toxicity. Expression of a dominant negative mutant or RNAi knockdown of BNIP3 protected the cells from cyanide. It was concluded that cyanide activated the HIF-1α-mediated pathway of BNIP3 induction through a redox-sensitive process. Increased BNIP3 expression then served as an initiator of mitochondrial-mediated death.

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Section: Discussionsupporting

confidence: 53%

“…Apoptosis was detected by nuclear staining with Hoechst 33258 as described previously [22]. Cells were washed twice with phosphate-buffered saline (PBS), and fixed in 4% paraformaldehyde in PBS, then treated with 2 μM Hoechst 33258 dye and examined under fluorescence microscopy.…”

Section: Cell Death Assaymentioning

confidence: 99%

HIF-1α activation by a redox-sensitive pathway mediates cyanide-induced BNIP3 upregulation and mitochondrial-dependent cell death

Zhang

Liu

et al. 2007

Free Radical Biology and Medicine

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“…Other studies have shown that BNIP3 induction can be activated by non-hypoxia pathways by activating HIF-1α signaling by non-oxygen mediated pathways involving kinase signaling pathways perhaps stimulated by oxidative stress (Yook et al, 2004;Kanzawa et al, 2005;An et al, 2006). The intense oxidative stress produced by cyanide as a result of complex IV inhibition may be the BNIP3 activation stimulus (Jones et al, 2003;Chen et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

“…Cyanide is a rapid-acting neurotoxicant that inhibits cytochrome oxidase (complex IV) to block mitochondrial respiration, leading to lowering of ΔΨ m, reduced ATP levels and enhanced intracellular reactive oxygen species (ROS) generation (Jones et al, 2003). Cyanide can produce two distinct modes of death in the nervous system, depending on cell type and level of oxidative insult (Mills et al, 1999;Prabhakaran et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Upregulation of BNIP3 and translocation to mitochondria mediates cyanide-induced apoptosis in cortical cells

Prabhakaran

Zhang

et al. 2007

Neuroscience

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BNIP3, a BH3 domain only Bcl-2 protein, has been identified as a mitochrondrial mediator of hypoxia-induced cell death. Since cyanide produces histotoxic anoxia (chemical hypoxia), the present study was undertaken in primary cortical cells to determine involvement of the BNIP3 signaling pathway in cyanide-induced death. Over a 20 h exposure KCN increased BNIP3 expression, followed by a concentration-related apoptotic death. To determine if BNIP3 plays a role in the cell death, expression was either overexpressed with BNIP3 cDNA (BNIP3 + ) or knocked down with small interfering RNA (RNAi). In BNIP3 + cells, cyanide-induced apoptotic death was markedly enhanced and preceded by reduction of mitochondrial membrane potential (Δψ m ), release of cytochrome c from mitochondria and elevated caspase 3 and 7 activity. Pretreatment with the pan caspase inhibitor zVAD-fmk suppressed BNIP3 + -mediated cell death, thus confirming a caspasedependent apoptosis. On the other hand, BNIP3 knock down by RNAi or antagonism of BNIP3 by a transmembrane-deleted dominant-negative mutant (BNIP3ΔTM) markedly reduced cell death. Immunohistochemical imaging showed that cyanide stimulated translocation of BNIP3 from cytosol to mitochondria and displacement studies with BNIP3ΔTM showed that integration of BNIP3 into the mitochondrial outer membrane was necessary for the cell death. In BNIP3 + cells, cyclosporin-A, an inhibitor of mitochondrial pore transition, blocked the cyanide-induced reduction of Δψ m and decreased the apoptotic death. These results demonstrate in cortical cells that cyanide induces a rapid upregulation of BNIP3 expression, followed by translocation to the mitochondrial outer membrane to reduceΔψ m This was followed by mitochondrial release of cytochrome c to execute a caspasedependent cell death.

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“…Cyanide-induced activation of NMDA receptor produces simultaneous generation of NO and reactive oxygen species, leading to cellular oxidative stress and cytotoxicity (19,20). Moreover, cyanide (100 mM) has been reported to enhance dopamine-induced apoptosis in PC12 cells and fetal rat mesencephalic cells (21,22). However, apoptosis is reduced by pre-incubation with antioxidants superoxide dismutase and glutathione catalase, the nitric oxide synthase inhibitor N o -nitro-L-arginine methyl ester, and the peroxynitrite scavenger uric acid.…”

mentioning

confidence: 99%

Is there evidence that cyanide can act as a neuromodulator?

Cipollone

Visca

2007

IUBMB Life

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Is There an Answer? is intended to serve as a forum in which readers to IUBMB Life may pose questions of the type that intrigue biochemists but for which there may be no obvious answer or one may be available but not widely known or easily accessible. Readers are invited to e‐mail ascenzi@uniroma3.it if they have questions to contribute or if they can provide answers to questions that are provided here from time to time. In the latter case, instructions will be sent to interested readers. Answers should be, whenever possible, evidence‐based and provide relevant references. Paolo Ascenzi

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Cyanide Enhancement of Dopamine-Induced Apoptosis in Mesencephalic Cells Involves Mitochondrial Dysfunction and Oxidative Stress

Cited by 41 publications

References 40 publications

HIF-1α activation by a redox-sensitive pathway mediates cyanide-induced BNIP3 upregulation and mitochondrial-dependent cell death

HIF-1α activation by a redox-sensitive pathway mediates cyanide-induced BNIP3 upregulation and mitochondrial-dependent cell death

Upregulation of BNIP3 and translocation to mitochondria mediates cyanide-induced apoptosis in cortical cells

Is there evidence that cyanide can act as a neuromodulator?

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