Biomedical subjects

Navdeep S Chandel

Publications and source records attributed to Navdeep S Chandel.

At least 19 recordsLinked to original sources

PubMed2025

Mitochondrial activity tunes nociceptor resilience to excitotoxicity.

The capsaicin receptor, TRPV1, mediates the detection of noxious chemical and thermal stimuli by nociceptors, primary sensory neurons of the pain pathway. Overactivation of TRPV1 leads to cellular damage or death through calcium entry and excitotoxicity. We have exploited this phenomenon to conduct a systematic analysis of excitotoxicity through a genome-wide CRISPRi screen, thereby revealing a comprehensive network of regulatory pathways. We show that decreased expression of mitochondrial electron transport chain (ETC) components protects against capsaicin-induced toxicity and other challenges by mitigating both calcium imbalance and the generation of mitochondrial reactive oxygen species via distinct pathways. Moreover, we confirm the regulatory roles of the ETC in sensory neurons through gain-of-function and loss-of-function experiments. Interestingly, TRPV1+ sensory neurons maintain lower expression of ETC components and can better tolerate excitotoxicity and oxidative stress compared with other sensory neuron subtypes, implicating ETC tuning as an intrinsic cellular strategy that protects nociceptors against excitotoxicity.

Mitochondria↗

PubMed2006

Leptin resistance protects mice from hyperoxia-induced acute lung injury.

RATIONALE: Human data suggest that the incidence of acute lung injury is reduced in patients with type II diabetes mellitus. However, the mechanisms by which diabetes confers protection from lung injury are unknown. OBJECTIVES: To determine whether leptin resistance, which is seen in humans with diabetes, protects mice from hyperoxic lung injury. METHODS: Wild-type (leptin responsive) and db/db (leptin resistant) mice were used in these studies. Mice were exposed to hyperoxia (100% O(2)) for 84 hours to induce lung injury and up to 168 hours for survival studies. Alveolar fluid clearance was measured in vivo. MEASUREMENTS AND MAIN RESULTS: Lung leptin levels were increased both in wild-type and leptin receptor-defective db/db mice after hyperoxia. Hyperoxia-induced lung injury was decreased in db/db compared with wild-type mice. Hyperoxia increased lung permeability in wild-type mice but not in db/db mice. Compared with wild-type control animals, db/db mice were resistant to hyperoxia-induced mortality (lethal dose for 50% of mice, 152 vs. 108 h). Intratracheal instillation of leptin at a dose that was observed in the bronchoalveolar lavage fluid during hyperoxia caused lung injury in wild-type but not in db/db mice. Intratracheal pretreatment with a leptin receptor inhibitor attenuated leptin-induced lung edema. The hyperoxia-induced release of proinflammatory cytokines was attenuated in db/db mice. Despite resistance to lung injury, db/db mice had diminished alveolar fluid clearance and reduced Na,K-ATPase function compared with wild-type mice. CONCLUSIONS: These results indicate that leptin can induce and that resistance to leptin attenuates hyperoxia-induced lung injury and hyperoxia-induced inflammatory cytokines in the lung.

Animals↗

PubMed2006

Loss of Mcl-1 protein and inhibition of electron transport chain together induce anoxic cell death.

How cells die in the absence of oxygen (anoxia) is not understood. Here we report that cells deficient in Bax and Bak or caspase-9 do not undergo anoxia-induced cell death. However, the caspase-9 null cells do not survive reoxygenation due to the generation of mitochondrial reactive oxygen species. The individual loss of Bim, Bid, Puma, Noxa, Bad, caspase-2, or hypoxia-inducible factor 1beta, which are potential upstream regulators of Bax or Bak, did not prevent anoxia-induced cell death. Anoxia triggered the loss of the Mcl-1 protein upstream of Bax/Bak activation. Cells containing a mitochondrial DNA cytochrome b 4-base-pair deletion ([rho(-)] cells) and cells depleted of their entire mitochondrial DNA ([rho(0)] cells) are oxidative phosphorylation incompetent and displayed loss of the Mcl-1 protein under anoxia. [rho(0)] cells, in contrast to [rho(-)] cells, did not die under anoxia. However, [rho(0)] cells did undergo cell death in the presence of the Bad BH3 peptide, an inhibitor of Bcl-X(L)/Bcl-2 proteins. These results indicate that [rho(0)] cells survive under anoxia despite the loss of Mcl-1 protein due to residual prosurvival activity of the Bcl-X(L)/Bcl-2 proteins. Collectively, these results demonstrate that anoxia-induced cell death requires the loss of Mcl-1 protein and inhibition of the electron transport chain to negate Bcl-X(L)/Bcl-2 proteins.

Adaptation, Physiological↗

PubMed2006

The cellular basis for diverse responses to oxygen.

Mammalian cells have divergent responses to varying oxygen levels. Cells exposed to low oxygen levels (hypoxia) activate the transcription factor hypoxia-inducible factor-1 (HIF-1) as an adaptive response. Cells exposed to hypoxia do not undergo senescence or cell death and do not diminish ATP levels. By contrast, cells exposed to high oxygen levels (hyperoxia) undergo senescence and cell death and decrease their ATP levels, yet do not activate HIF-1. Despite these divergent responses with respect to senescence, cell death, metabolism, and gene expression, the signaling events in both systems are mediated by the generation of mitochondrial-derived reactive oxygen species (ROS). This perspective reviews the role of signaling through mitochondrial ROS in hypoxic and hyperoxic environments.

Animals↗

PubMed2006

Hypoxia-mediated degradation of Na,K-ATPase via mitochondrial reactive oxygen species and the ubiquitin-conjugating system.

We set out to determine whether cellular hypoxia, via mitochondrial reactive oxygen species, promotes Na,K-ATPase degradation via the ubiquitin-conjugating system. Cells exposed to 1.5% O2 had a decrease in Na,K-ATPase activity and oxygen consumption. The total cell pool of alpha1 Na,K-ATPase protein decreased on exposure to 1.5% O2 for 30 hours, whereas the plasma membrane Na,K-ATPase was 50% degraded after 2 hours of hypoxia, which was prevented by lysosome and proteasome inhibitors. When Chinese hamster ovary cells that exhibit a temperature-sensitive defect in E1 ubiquitin conjugation enzyme were incubated at 40 degrees C and 1.5% O2, the degradation of the alpha1 Na,K-ATPase was prevented. Exogenous reactive oxygen species increased the plasma membrane Na,K-ATPase degradation, whereas, in mitochondrial DNA deficient rho(0) cells and in cells transfected with small interfering RNA against Rieske iron sulfur protein, the hypoxia-mediated Na,K-ATPase degradation was prevented. The catalase/superoxide dismutase (SOD) mimetic (EUK-134) and glutathione peroxidase overexpression prevented the hypoxia-mediated Na,K-ATPase degradation and overexpression of SOD1, but not SOD2, partially inhibited the Na+ pump degradation. Accordingly, we provide evidence that during hypoxia, mitochondrial reactive oxygen species are necessary to degrade the plasma membrane Na,K-ATPase via the ubiquitin-conjugating system.

Animals↗

PubMed2006

Proapoptotic Bid is required for pulmonary fibrosis.

The molecular mechanisms of pulmonary fibrosis are poorly understood. Previous reports indicate that activation of TGF-beta1 is essential for the development of pulmonary fibrosis. Here, we report that the proapoptotic Bcl-2 family member Bid is required for the development of pulmonary fibrosis after the intratracheal instillation of bleomycin. Mice lacking Bid exhibited significantly less pulmonary fibrosis in response to bleomycin compared with WT mice. The attenuation in pulmonary fibrosis was observed despite similar levels of inflammation, lung injury, and active TGF-beta1 in bronchoalveolar lavage fluid 5 days after the administration of bleomycin in mice lacking Bid and in WT controls. Bleomycin induced similar levels cell death in vitro in alveolar epithelial cells isolated from WT and bid(-/-) mice. By contrast, alveolar epithelial cells from bid(-/-) mice were resistant to TGF-beta1-induced cell death. These results indicate that Bcl-2 family members are critical regulators for the development of pulmonary fibrosis downstream of TGF-beta1 activation.

Animals↗

PubMed2006

Airborne particulate matter inhibits alveolar fluid reabsorption in mice via oxidant generation.

Ambient particulate matter is increasingly recognized as a significant contributor to human cardiopulmonary morbidity and mortality in the United States and worldwide. We sought to determine whether exposure to ambient particulate matter would alter alveolar fluid clearance in mice. Mice were exposed to a range of doses of a well-characterized particulate matter collected from the ambient air in Düsseldorf, Germany through a single intratracheal instillation, and alveolar fluid clearance and measurements of lung injury were made. Exposure to even very low doses of particulate matter (10 microg) resulted in a significant reduction in alveolar fluid clearance that was maximal 24 h after the exposure, with complete resolution after 7 d. This was paralleled by a decrease in lung Na,K-ATPase activity. To investigate the mechanism of this effect, we measured plasma membrane Na,K-ATPase abundance in A549 cells and Na,K-ATPase activity in primary rat alveolar type II cells after exposure to particulate matter in the presence or absence of the combined superoxide dismutase and catalase mimetic EUK-134 (5 microM). Membrane but not total protein abundance of the Na,K-ATPase was decreased after exposure to particulate matter, as was Na,K-ATPase activity. This decrease was prevented by the combined superoxide dismutase/catalase mimetic EUK-134. The intratracheal instillation of particulate matter results in alveolar epithelial injury and decreased alveolar fluid clearance, conceivably due to downregulation of the Na,K-ATPase.

Air Pollutants↗

PubMed2005

Intrinsic mechanism of estradiol-induced apoptosis in breast cancer cells resistant to estrogen deprivation.

BACKGROUND: We previously developed an estrogen receptor (ER)-positive breast cancer cell line (MCF-7:5C) that is resistant to long-term estrogen deprivation and undergoes rapid and complete apoptosis in the presence of physiologic concentrations of 17beta-estradiol. Here, we investigated the role of the mitochondrial apoptotic pathway in this process. METHODS: Apoptosis in MCF-7:5C cells treated with estradiol, fulvestrant, or vehicle (control) was investigated by annexin V-propidium iodide double staining and 4',6-diamidino-2-phenylindole (DAPI) staining. Apoptosis was also analyzed in MCF-7:5C cells transiently transfected with small interfering RNAs (siRNAs) to apoptotic pathway components. Expression of apoptotic pathway intermediates was measured by western blot analysis. Mitochondrial transmembrane potential (psim) was determined by rhodamine-123 retention assay. Mitochondrial pathway activity was determined by cytochrome c release and cleavage of poly(ADP-ribose) polymerase (PARP) protein. Tumorigenesis was studied in ovariectomized athymic mice that were injected with MCF-7:5C cells. Differences between the treatment groups and control group were determined by two-sample t test or one-factor analysis of variance. All statistical tests were two-sided. RESULTS: MCF-7:5C cells treated with estradiol underwent apoptosis and showed increased expression of proapoptotic proteins, decreased psim, enhanced cytochrome c release, and PARP cleavage compared with cells treated with fulvestrant or vehicle. Blockade of Bax, Bim, and p53 mRNA expression by siRNA reduced estradiol-induced apoptosis relative to control by 76% [95% confidence interval (CI) = 73% to 79%, P < .001], 85% [95% CI = 90% to 80%, P < .001], and 40% [95% CI = 45% to 35%, P < .001], respectively, whereas blockade of FasL by siRNA had no effect. Estradiol caused complete regression of MCF-7:5C tumors in vivo. CONCLUSION: The mitochondrial pathway of apoptosis plays a critical role in estradiol-induced apoptosis in long-term estrogen-deprived breast cancer cells. Physiologic concentrations of estradiol could potentially be used to induce apoptosis and tumor regression in tumors that have developed resistance to aromatase inhibitors.

Annexin A5↗

PubMed2005

Oxygen sensing: getting pumped by sterols.

Oxygen plays a pivotal role in the maintenance of life for all eukaryotes, with the exception of strict anaerobes. Eukaryotes have developed mechanisms to sense and respond to decreased oxygen levels. How eukaryotes sense oxygen is still not fully understood. What is (or are) the oxygen sensor(s)? This question has vital physiological and pathophysiological implications, because all living aerobic organisms have adaptive mechanisms to maintain oxygen homeostasis. A recent report describes a novel eukaryotic oxygen-sensing mechanism in the fission yeast Schizosaccharomyces pombe, involving the depletion of sterols as a trigger to induce gene expression in response to decreased oxygen levels. It is not yet clear whether this mechanism is involved in the mammalian response to hypoxia, possibly in conjunction with activation of one or both of the hypoxia-inducible factor (HIF-1 or HIF-2) transcription factors.

Aerobiosis↗

PubMed2005

Oxygen sensing requires mitochondrial ROS but not oxidative phosphorylation.

Mammalian cells detect decreases in oxygen concentrations to activate a variety of responses that help cells adapt to low oxygen levels (hypoxia). One such response is stabilization of the protein HIF-1 alpha, a component of the transcription factor HIF-1. Here we show that a small interfering RNA (siRNA) against the Rieske iron-sulfur protein of mitochondrial complex III prevents the hypoxic stabilization of HIF-1 alpha protein. Fibroblasts from a patient with Leigh's syndrome, which display residual levels of electron transport activity and are incompetent in oxidative phosphorylation, stabilize HIF-1 alpha during hypoxia. The expression of glutathione peroxidase or catalase, but not superoxide dismutase 1 or 2, prevents the hypoxic stabilization of HIF-1 alpha. These findings provide genetic evidence that oxygen sensing is dependent on mitochondrial-generated reactive oxygen species (ROS) but independent of oxidative phosphorylation.

Electron Transport Complex III↗

PubMed2005

Mitochondrial regulation of oxygen sensing.

Maintenance of oxygen homoeostasis is required for the survival of higher organisms. The transcription factor hypoxia inducible factor (HIF) has a crucial role in oxygen homoeostasis by integrating the decrease in oxygen levels to increase hypoxic gene expression. How cells sense decrease in oxygen levels to elicit an increase in HIF dependent gene expression is not fully understood. In this review, we discuss the role of mitochondria as oxygen sensors regulating HIF.

Animals↗

PubMed2005

Mitochondrial reactive oxygen species activation of p38 mitogen-activated protein kinase is required for hypoxia signaling.

Mammalian cells have the ability to sense low oxygen levels (hypoxia). An adaptive response to hypoxia involves the induction of the transcription factor hypoxia-inducible factor 1 (HIF-1). The intracellular signaling pathways that regulate HIF-1 activation during hypoxia remain unknown. Here, we demonstrate that p38alpha-/- cells fail to activate HIF-1 under hypoxic conditions. Cells deficient in Mkk3 and Mkk6, the upstream regulators of p38alpha, also fail to activate HIF-1 under hypoxic conditions. The p38alpha-/- cells are able to activate HIF-1 in response to anoxia or iron chelators during normoxia. Furthermore, the hypoxic activation of p38alpha and HIF-1 was abolished by myxothiazol, a mitochondrial complex III inhibitor, and glutathione peroxidase 1 (GPX1), a scavenger of hydrogen peroxide. Thus, the activation of p38alpha and HIF-1 is dependent on the generation of mitochondrial reactive oxygen species. These results provide genetic evidence that p38 mitogen-activated protein kinase signaling is essential for HIF-1 activation.

Animals↗

PubMed2005

Bleomycin induces alveolar epithelial cell death through JNK-dependent activation of the mitochondrial death pathway.

Exposure to bleomycin in rodents induces lung injury and fibrosis. Alveolar epithelial cell death has been hypothesized as an initiating mechanism underlying bleomycin-induced lung injury and fibrosis. In the present study we evaluated the contribution of mitochondrial and receptor-meditated death pathways in bleomycin-induced death of mouse alveolar epithelial cells (MLE-12 cells) and primary rat alveolar type II cells. Control MLE-12 cells and primary rat alveolar type II cells died after 48 h of exposure to bleomycin. Both MLE-12 cells and rat alveolar type II cells overexpressing Bcl-X(L) did not undergo cell death in response to bleomycin. Dominant negative Fas-associating protein with a death domain failed to prevent bleomycin-induced cell death in MLE-12 cells. Caspase-8 inhibitor CrmA did not prevent bleomycin-induced cell death in primary rat alveolar type II cells. Furthermore, fibroblast cells deficient in Bax and Bak, but not Bid, were resistant to bleomycin-induced cell death. To determine whether the stress kinase JNK was an upstream regulator of Bax activation, MLE-12 cells were exposed to bleomycin in the presence of an adenovirus encoding a dominant negative JNK. Bleomycin-induced Bax activation was prevented by the expression of a dominant negative JNK in MLE-12 cells. Dominant negative JNK prevented cell death in MLE-12 cells and in primary rat alveolar type II cells exposed to bleomycin. These data indicate that bleomycin induces cell death through a JNK-dependent mitochondrial death pathway in alveolar epithelial cells.

Adaptor Proteins, Signal Transducing↗

PubMed2004

Hexokinase-mitochondria interaction mediated by Akt is required to inhibit apoptosis in the presence or absence of Bax and Bak.

The serine/threonine kinase Akt inhibits mitochondrial cytochrome c release and apoptosis induced by a variety of proapoptotic stimuli. The antiapoptotic activity of Akt is coupled, at least in part, to its effects on cellular metabolism. Here, we provide genetic evidence that Akt is required to maintain hexokinase association with mitochondria. Targeted disruption of this association impairs the ability of growth factors and Akt to inhibit cytochrome c release and apoptosis. Targeted disruption of mitochondria-hexokinase (HK) interaction or exposure to proapoptotic stimuli that promote rapid dissociation of hexokinase from mitochondria potently induce cytochrome c release and apoptosis, even in the absence of Bax and Bak. These effects are inhibited by activated Akt, but not by Bcl-2, implying that changes in outer mitochondrial membrane (OMM) permeability leading to apoptosis can occur in the absence of Bax and Bak and that Akt inhibits these changes through maintenance of hexokinase association with mitochondria.

Animals↗

PubMed2004

Active transforming growth factor-beta1 activates the procollagen I promoter in patients with acute lung injury.

OBJECTIVE: Fibroproliferation markers like procollagen I predict mortality in patients with acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). We sought to determine whether bronchoalveolar lavage fluid (BALF) from patients with lung injury contained mediators that would activate procollagen I promoter and if this activation predicted important clinical outcomes. DESIGN: Prospective controlled study of ALI/ARDS. SETTING: Intensive care units and laboratory of a university hospital. PATIENTS AND PARTICIPANTS: Acute lung injury/ARDS, cardiogenic edema (negative controls) and pulmonary fibrosis (positive controls) patients. INTERVENTIONS: Bronchoalveolar lavage fluid was collected within 48 h of intubation from ALI/ARDS patients. BALF was also collected from patients with pulmonary fibrosis and cardiogenic pulmonary edema. Human lung fibroblasts were transfected with a procollagen I promoter-luciferase construct and incubated with BALF; procollagen I promoter activity was then measured. BALF active TGF-beta1 levels were measured by ELISA. RESULTS: Twenty-nine ARDS patients, nine negative and six positive controls were enrolled. BALF from ARDS patients induced 41% greater procollagen I promoter activation than that from negative controls (p<0.05) and a TGF-beta1 blocking antibody significantly reduced this activation in ARDS patients. There was a trend toward higher TGF-beta1 levels in the ARDS group compared to negative controls (-1.056 log(10)+/-0.1415 vs -1.505 log(10)+/-0.1425) (p<0.09). Procollagen I promoter activation was not associated with mortality; however, lower TGF-beta1 levels were associated with more ventilator-free and ICU-free days. CONCLUSIONS: Bronchoalveolar lavage fluid from ALI/ARDS patients activates procollagen I promoter, which is due partly to TGF-beta1. Activated TGF-beta1 may impact ARDS outcome independent of its effect on procollagen I activation.

Bronchoalveolar Lavage Fluid↗

PubMed2004

Follicle-stimulating hormone activation of hypoxia-inducible factor-1 by the phosphatidylinositol 3-kinase/AKT/Ras homolog enriched in brain (Rheb)/mammalian target of rapamycin (mTOR) pathway is necessary for induction of select protein markers of follicular differentiation.

We sought to elucidate the role of AKT in follicle-stimulating hormone (FSH)-mediated granulosa cell (GC) differentiation. Our results define a signaling pathway in GCs whereby the inactivating phosphorylation of tuberin downstream of phosphatidylinositol (PI) 3-kinase/AKT activity leads to Rheb (Ras homolog enriched in brain) and subsequent mTOR (mammalian target of rapamycin) activation. mTOR then stimulates translation by phosphorylating p70 S6 kinase and, consequently, the 40 S ribosomal protein S6. Activation of this pathway is required for FSH-mediated induction of several follicular differentiation markers, including luteinizing-hormone receptor (LHR), inhibin-alpha, microtubule-associated protein 2D, and the PKA type IIbeta regulatory subunit. FSH also promotes activation of the transcription factor hypoxia-inducible factor-1 (HIF-1). FSH-stimulated HIF-1 activity is inhibited by the PI 3-kinase inhibitor LY294002, the Rheb inhibitor FTI-277 (farnesyltransferase inhibitor-277), and the mTOR inhibitor rapamycin. Finally, we find that the FSH-mediated up-regulation of reporter activities for LHR, inhibin-alpha, and vascular endothelial growth factor is dependent upon HIF-1 activity, because a dominant negative form of HIF-1alpha interferes with the up-regulation of these genes. These results show that FSH enhances HIF-1 activity downstream of the PI 3-kinase/AKT/Rheb/mTOR pathway in GCs and that HIF-1 activity is necessary for FSH to induce multiple follicular differentiation markers.

Animals↗

PubMed2004

Mitochondrial-derived free radicals mediate asbestos-induced alveolar epithelial cell apoptosis.

Asbestos causes pulmonary toxicity by mechanisms that in part involve reactive oxygen species (ROS). However, the precise source of ROS is unclear. We showed that asbestos induces alveolar epithelial cell (AEC) apoptosis by a mitochondrial-regulated death pathway. To determine whether mitochondrial-derived ROS are necessary for causing asbestos-induced AEC apoptosis, we utilized A549-rho(omicron) cells that lack mitochondrial DNA and a functional electron transport. As expected, antimycin, which induces an oxidative stress by blocking mitochondrial electron transport at complex III, increased dichlorofluoroscein (DCF) fluorescence in A549 cells but not in A549-rho(omicron) cells. Compared with A549 cells, rho(omicron) cells have less asbestos-induced ROS production, as assessed by DCF fluorescence, and reductions in total glutathione levels as well as less caspase-9 activation and apoptosis, as assessed by TdT-mediated dUTP nick end labeling staining and DNA fragmentation. A mitochondrial anion channel inhibitor that prevents ROS release from the mitochondria to the cytoplasm also blocked asbestos-induced A549 cell caspase-9 activation and apoptosis. Finally, a role for nonmitochondrial-derived ROS with exposure to high levels of asbestos (50 microg/cm(2)) was suggested by our findings that an iron chelator (phytic acid or deferoxamine) or a free radical scavenger (sodium benzoate) provided additional protection against asbestos-induced caspase-9 activation and DNA fragmentation in rho(omicron) cells. We conclude that asbestos fibers affect mitochondrial DNA and functional electron transport, resulting in mitochondrial-derived ROS production that in turn mediates AEC apoptosis. Nonmitochondrial-associated ROS may also contribute to AEC apoptosis, particularly with high levels of asbestos exposure.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗

PubMed2003

c-Myc sensitization to oxygen deprivation-induced cell death is dependent on Bax/Bak, but is independent of p53 and hypoxia-inducible factor-1.

Deregulated expression of c-Myc can sensitize cells to a variety of death stimuli, including loss of growth factors and oxygen. In this study, we examined whether rodent fibroblasts that conditionally express c-Myc undergo a similar mechanism of cell death in response to serum or oxygen deprivation. Our results demonstrate that murine embryonic fibroblasts from bax-/-bak-/- mice that conditionally express c-Myc did not die in response to either oxygen or serum deprivation. Fibroblasts from p53-/- mice that conditionally express c-Myc died in response to oxygen (but not serum) deprivation. The inability of p53 to regulate oxygen deprivation-induced cell death was due to the lack of induction of p53 target genes Puma, Noxa, and Pten. In contrast, serum deprivation transcriptionally induced Puma and Pten in cells that conditionally express c-Myc. The failure of p53 to regulate oxygen deprivation-induced cell death led us to hypothesize whether hypoxia-inducible factor (HIF) might be a critical regulator of cell death during oxygen deprivation. Fibroblasts from HIF-1beta-/- cells that conditionally express c-Myc were not able to transcriptionally activate HIF during oxygen deprivation. These cells died in response to oxygen deprivation. Thus, oxygen deprivation-induced cell death in fibroblasts with deregulated expression of c-Myc is independent of p53 or HIF-1 status, but is dependent on the Bcl-2 family member Bax or Bak to initiate mitochondrial dependent cell death.

Animals↗