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

Zhang, Lenan; Li, L.; Liu, Huinan; Prabhakaran, Krishnan; Zhang, X.; Borowitz, Joseph L.; Isom, Gary E.

doi:10.1016/j.freeradbiomed.2007.04.005

Cited by 57 publications

(45 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…An et al (2) have previously shown that whereas U0126, a specific MEK inhibitor, completely abolished BNIP3 expression and the stimulation of promoter activity by NO and Ras in macrophages, the specific inhibitor of p38 MAPK SB 203580 had no effect. In contrast, the same selective p38 MAPK inhibitor blocked the activation of both the p38 MAPK and the HRE promoter necessary for nuclear accumulation of HIF-1␣ and BNIP3 gene transcription following exposure to cyanide in an immortalized dopaminergic cell line (56). Our results showing that the p38 MAPK inhibitor SB 203580 blocked the hypoxia-mediated upregulation of BNIP3 suggest that activation of the p38 MAPK pathway, but not the JNK pathway, is necessary for BNIP3 protein upregulation under hypoxic conditions.…”

Section: Discussionmentioning

confidence: 58%

Expression and subcellular localization of BNIP3 in hypoxic hepatocytes and liver stress

Metukuri¹,

Beer‐Stolz²,

Namas³

et al. 2009

American Journal of Physiology-Gastrointestinal and Liver Physi

View full text Add to dashboard Cite

We have previously demonstrated that the Bcl-2/adenovirus EIB 19-kDa interacting protein 3 (BNIP3), a cell death-related member of the Bcl-2 family, is upregulated in vitro and in vivo in both experimental and clinical settings of redox stress and that nitric oxide (NO) downregulates its expression. In this study we sought to examine the expression and localization of BNIP3 in murine hepatocytes and in a murine model of hemorrhagic shock (HS) and ischemia-reperfusion (I/R). Freshly isolated mouse hepatocytes were exposed to 1% hypoxia for 6 h followed by reoxygenation for 18 h, and protein was isolated for Western blot analysis. Hepatocytes grown on coverslips were fixed for localization studies. Similarly, livers from surgically cannulated C57Bl/6 mice and from mice cannulated and subjected to 1-4 h of HS were processed for protein isolation and Western blot analysis. In hepatocytes, BNIP3 was expressed constitutively but was upregulated under hypoxic conditions, and this upregulation was countered by treatment with a NO donor. Surprisingly, BNIP3 was localized in the nucleus of normoxic hepatocytes, in the cytoplasm following hypoxia, and again in the nucleus following reoxygenation. Upregulation of BNIP3 partially required p38 MAPK activation. BNIP3 contributed to hypoxic injury in hepatocytes, since this injury was diminished by knockdown of BNIP3 mRNA. Hepatic BNIP3 was also upregulated in two different models of liver stress in vivo, suggesting that a multitude of inflammatory stresses can lead to the modulation of BNIP3. In turn, the upregulation of BNIP3 appears to be one mechanism of hepatocyte cell death and liver damage in these settings. redox stress; nitric oxide; hypoxia; cell death; inflammation THE BCL-2/ADENOVIRUS EIB 19-kDa interacting protein 3 (BNIP3, formerly known as NIP3) was first identified in a yeast twohybrid screen as a protein capable of interacting with the adenovirus protein E1B 19 kDa, a homolog of Bcl-2 (4). BNIP3 is a membrane-associated protein localized to mitochondria and other cytoplasmic membrane structures and is widely expressed in a large number of mouse and human tissues (8). BNIP3 appears to have an overall resemblance to several BH3-containing Bcl-2 family proteins such as BIK, BID, HRK, and BAD, in which the BH3 domain plays an important role in the induction of apoptosis. However, BNIP3 has been implicated in both apoptotic and necrotic cell death (5). For instance, the expression of BNIP3 (both mRNA and protein) is induced and related to hypoxia-induced apoptosis in a number of human and animal cell lines, including CHO-K1 (Chinese hamster ovary), CV-1 (monkey kidney), Rat-1 (rat fibroblast), PAM212 (human epithelial), HepG2 (human hepatocellular carcinoma), and ECV-304 (human bladder carcinoma) (5). Moreover, BNIP3 and Nix [a BNIP3 homolog sharing both structural and functional similarity (7), also known as BNIP3L (30), BNIP3␣ (50), and B5 (35)] are the only members of the Bcl-2 family of apoptotic factors induced in response to hypoxia (5). On the other hand, BNI...

show abstract

Section: Discussionmentioning

confidence: 58%

Expression and subcellular localization of BNIP3 in hypoxic hepatocytes and liver stress

Metukuri¹,

Beer‐Stolz²,

Namas³

et al. 2009

American Journal of Physiology-Gastrointestinal and Liver Physi

View full text Add to dashboard Cite

show abstract

“…However, treatment of the tissues with NAC fully reversed the E GSH to normality, but normalization of the redox status did not modify their neurosecretory power. These last observations coupled to the well known ability of NAC to buffer the increased production of ROS induced by complex III and IV inhibitors in many cell systems (Watabe and Nakaki, 2007;Stöckl et al, 2006;Suzuki et al, 1998;Satpute et al, 2008;Zhang et al, 2007), would indicate that there is not any relationship between ROS levels and chemoreceptor cell activity.…”

Section: Discussionmentioning

confidence: 99%

Effects of mitochondrial poisons on glutathione redox potential and carotid body chemoreceptor activity

Gomez-Niño

Agapito

Obeso

et al. 2009

Respiratory Physiology & Neurobiology

View full text Add to dashboard Cite

a b s t r a c tLow oxygen sensing in chemoreceptor cells involves the inhibition of specific plasma membrane K + channels, suggesting that mitochondria-derived reactive oxygen species (ROS) link hypoxia to K + channel inhibition, subsequent cell depolarization and activation of neurotransmitter release. We have used several mitochondrial poisons, alone and in combination with the antioxidant N-acetylcysteine (NAC), and quantify their capacity to alter GSH/GSSG levels and glutathione redox potential (E GSH ) in rat diaphragm. Selected concentrations of mitochondrial poisons with or without NAC were tested for their capacity to activate neurotransmitter release in chemoreceptor cells and to alter ATP levels in intact rat carotid body (CB). We found that rotenone (1 M), antimycin A (0.2 g/ml) and sodium azide (5 mM) decreased E GSH ; NAC restored E GSH to control values. At those concentrations mitochondrial poisons activated neurotransmitter release from CB chemoreceptor cells and decreased CB ATP levels, NAC being ineffective to modify these responses. Additional experiments with 3-nitroprionate (5 mM), lower concentrations of rotenone and dinitrophenol revealed variable relationships between E GSH and chemoreceptor cell neurotransmitter release responses and ATP levels. These findings indicate a lack of correlation between mitochondrialgenerated modifications of E GSH and chemoreceptor cells activity. This lack of correlation renders unlikely that alteration of mitochondrial production of ROS is the physiological pathway chemoreceptor cells use to signal hypoxia.

show abstract

“…The JC-1-stained cells referred to above were processed to measure the green/red fluorescent intensity ratio as described previously (55). Briefly, at the end of the JC-1 experiment as mentioned above, cells were seeded in a 96-well plate (flat, clear bottom, Corning) at a density of 50,000 cells/well.…”

Section: Methodsmentioning

confidence: 99%

Cyclophilin D gene ablation protects mice from ischemic renal injury

Devalaraja-Narashimha

Diener²,

Padanilam

2009

American Journal of Physiology-Renal Physiology

110

View full text Add to dashboard Cite

Increased oxidative stress and intracellular calcium levels and mitochondrial overloading of calcium during ischemic renal injury (IRI) favor mitochondrial membrane permeability transition pore (MPTP) opening and subsequent necrotic cell death. Cyclophilin D (CypD) is an essential component of MPTP, and recent findings implicate its role in necrotic, but not apoptotic, cell death. To evaluate the role of CypD following IRI, we tested the hypothesis that CypD gene ablation protects mice from IRI. Renal function as assessed by plasma levels of both creatinine and blood urea nitrogen was significantly reduced in CypD knockout (CypD Ϫ/Ϫ ) mice compared with wild-type mice during the 5-day post-ischemia period. Erythrocyte trapping, tubular cell necrosis, tubular dilatation, and neutrophil infiltration were significantly decreased in CypD Ϫ/Ϫ mice. To define the mechanisms by which CypD deficiency protect the kidneys, an in vitro model of IRI was employed. Inhibition of CypD using Cyclosporin A in oxidant-injured cultured proximal tubular cells (PTC) prevented mitochondrial membrane depolarization, reduced LDH release, ATP depletion and necrotic cell death. Similarly, oxidant-injured CypD Ϫ/Ϫ PTC primary cultures were protected from cytotoxicity and necrosis. To conclude, CypD gene ablation offers both functional and morphological protection in mice following IRI by decreasing necrotic cell death possibly via inhibition of MPTP and ATP depletion. acute renal failure; mitochondria; ATP depletion APOPTOSIS AND NECROSIS COEXIST in ischemic renal tissues, and inhibition of either form of cell death in the setting of renal ischemia is shown to protect against renal dysfunction (13-16). The mechanisms by which renal cells undergo apoptosis or necrosis post-ischemic renal injury (IRI) are complex and incompletely defined. Necrotic cell death is widely considered to be an unregulated process that cannot be modulated by pharmacological means as opposed to apoptosis. However, recent reports challenge this tenet and indicate that necrosis can be regulated or "programmed" and can be prevented by targeting the molecular components of its signaling pathways (25).Permeability transition (PT) pores open in the mitochondrial inner membrane in response to stimuli such as increased intracellular Ca 2ϩ , inorganic phosphate, alkaline pH, and reactive oxygen species. IRI is associated with ATP depletion, increased reactive oxygen species, and intracellular calcium accumulation, conditions that favor mitochondrial membrane transition pore (MPTP) opening (17,28,35,56). Cyclophilin D (CypD) can associate with inner mitochondrial membrane proteins and regulate the mitochondrial permeability transition (MPT). MPT is a process in which a sudden increase in the inner mitochondrial membrane permeability allows solutes with a molecular mass Ͻ1,500 Da to enter the mitochondrial matrix, resulting in the loss of inner mitochondrial membrane potential and matrix swelling. Uncontrolled expansion of the matrix may eventually lead to rupture of the oute...

show abstract

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

Cited by 57 publications

References 43 publications

Expression and subcellular localization of BNIP3 in hypoxic hepatocytes and liver stress

Expression and subcellular localization of BNIP3 in hypoxic hepatocytes and liver stress

Effects of mitochondrial poisons on glutathione redox potential and carotid body chemoreceptor activity

Cyclophilin D gene ablation protects mice from ischemic renal injury

Contact Info

Product

Resources

About