JNK1/2 regulates ER–mitochondrial Ca2+ cross-talk during IL-1β–mediated cell death in RINm5F and human primary β-cells

Verma, Gaurav; Bhatia, Himanshi; Datta, Malabika

doi:10.1091/mbc.e12-12-0885

Cited by 26 publications

(21 citation statements)

References 57 publications

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“…4). The observations we have made in our diabetic embryopathy model system agree with findings in another recent study, which showed that inhibiting JNK1/2 prevented ER stress and apoptosis in pancreatic cells 130 . Therefore, our work has indicated a reciprocal causation between JNK1/2 and ER stress exists in pathogenesis of diabetic embryopathy (Fig.…”

Section: The Reciprocal Causation Between Jnk1/2 Activation and Er Stsupporting

confidence: 92%

Decoding the oxidative stress hypothesis in diabetic embryopathy through proapoptotic kinase signaling

Yang¹,

Reece²,

Wang³

et al. 2015

American Journal of Obstetrics and Gynecology

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Maternal diabetes-induced birth defects occur in 6-10% of babies born to mothers with pregestational diabetes, representing a significant maternal-fetal health problem. Currently, these congenital malformations represent a significant maternal-fetal medicine issue, but are likely to create an even greater public health threat as 3 million women of reproductive age (19-44 years) have diabetes in the United States alone, and this number is expected to double by 2030. Neural tube defects (NTDs) and congenital heart defects are the most common types of birth defects associated with maternal diabetes. Animal studies have revealed that embryos under hyperglycemic conditions exhibit high levels of oxidative stress resulting from enhanced production of reactive oxygen species and impaired antioxidant capability. Oxidative stress activates a set of pro-apoptotic kinase signaling intermediates leading to abnormal cell death in the embryonic neural tube, which causes NTD formation. Work in animal models also has revealed that maternal diabetes triggers a series of signaling intermediates: protein kinase C (PKC) isoforms, PKCα, βII and δ; apoptosis signal-regulating kinase 1 (ASK1), c-Jun-N-terminal kinase 1/2 (JNK1/2), caspase and apoptosis. Specifically, maternal diabetes in rodent models activates the pro-apoptotic unfolded protein response and endoplasmic reticulum (ER) stress. A reciprocal causation between JNK1/2 activation and ER stress exists in diabetic embryopathy. Molecular studies further demonstrate that deletion of the genes for PKCα, Ask1, Jnk1 or Jnk2 abolishes maternal diabetes-induced neural progenitor apoptosis and ameliorates NTD formation. Similar preventive effects are also observed when ASK1, JNK1/2 or ER stress is inhibited. Cell membrane stabilizers and antioxidant supplements are also effective in prevention of diabetes-induced birth defects. Mechanistic studies have revealed important insights into our understanding the cause of diabetic embryopathy and have provided a basis for future interventions against birth defects or other pregnancy complications associated with maternal diabetes. The knowledge of a molecular pathway map identified in animal studies has created unique opportunities to identify molecular targets for therapeutic intervention.

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Section: The Reciprocal Causation Between Jnk1/2 Activation and Er Stsupporting

confidence: 92%

Decoding the oxidative stress hypothesis in diabetic embryopathy through proapoptotic kinase signaling

Yang¹,

Reece²,

Wang³

et al. 2015

American Journal of Obstetrics and Gynecology

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“…Intracellular calcium levels were measured as described in the Fluo-4 Direct Calcium Assay kit (F10472, Invitrogen). 56 After seeding 5 Â 10 5 cells in 96-well plates, the medium was removed and 50 ml of prewarmed HBSS were added. The Fluo-4 Direct calcium reagent was prepared as described and added in a final concentration of 2.5 mM to the plate wells containing HBSS.…”

Section: Methodsmentioning

confidence: 99%

Mitochondrial metabolism directs stemness and differentiation in P19 embryonal carcinoma stem cells

et al. 2014

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The relationship between mitochondrial metabolism and cell viability and differentiation in stem cells (SCs) remains poorly understood. In the present study, we compared mitochondrial physiology and metabolism between P19SCs before/after differentiation and present a unique fingerprint of the association between mitochondrial activity, cell differentiation and stemness. In comparison with their differentiated counterparts, pluripotency of P19SCs was correlated with a strong glycolytic profile and decreased mitochondrial biogenesis and complexity: round, low-polarized and inactive mitochondria with a closed permeability transition pore. This decreased mitochondrial capacity increased their resistance against dichloroacetate. Thus, stimulation of mitochondrial function by growing P19SCs in glutamine/pyruvate-containing medium reduced their glycolytic phenotype, induced loss of pluripotent potential, compromised differentiation and became P19SCs sensitive to dichloroacetate. Because of the central role of this type of SCs in teratocarcinoma development, our findings highlight the importance of mitochondrial metabolism in stemness, proliferation, differentiation and chemoresistance. In addition, the present work suggests the regulation of mitochondrial metabolism as a tool for inducing cell differentiation in stem line therapies. Embryonal carcinoma cells, including the P19 cell line, are pluripotent cancer stem cells (CSCs) derived from pluripotent germ cell tumors called teratocarcinomas. These have been described as the malignant counterparts of embryonic stem cells (ESCs) and are considered a good model to study stem cell (SC) differentiation. The P19 cell line can be maintained as undifferentiated cells (P19SCs) or differentiated (P19dCs) to any cell type of the three germ layers. Similar to ESCs, P19 cells differentiate with retinoic acid (RA) in a dose-dependent manner and depending on growth conditions. 1 Although differentiation generally yields a mixed population of differentiated cells, P19 cells grown in monolayer and treated with 1 mM RA primarily differentiate in endoderm or mesoderm, while retaining their immortality. 2,3Although some therapeutic approaches for regenerative medicine and to targeting CSCs are based on differentiation 4 and mitochondrial-targeted therapies, 5,6 very little is known about the role of mitochondrial metabolism in SC maintenance and differentiation.7 Several mitochondrial characteristics that distinguish transformed cells from healthy cells have been described, 8 including increased mitochondrial transmembrane electric potential (Dcm), which may result from decreased mitochondrial ATP production under normoxia. Similarly, normal SCs primarily rely on glycolysis for energy supply, although the exact mechanism how this occurs in the presence of oxygen and the relationship between SC metabolism and cell fate control is not yet completely understood. 10Given the mitochondrial involvement in stemness and differentiation, 11 one can ask whether manipulation of mitochondrial physi...

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“…IL-1β is considered an important endogenous cytokine that can induce β-cell apoptosis and lead to the onset of diabetes by various pathways such as NO, 16 Ca2 + , 17 mitochondrial membrane potential, ROS 18 and endoplasmic reticulum stress (ERS). 19 The pro-apoptotic effect of IL-1β was observed in MIN 6 islet cells, which are mouse tumor cells expressing SV40 large T antigen under the control of an insulin promoter. Therefore, IL-1β-induced apoptosis has been used to evaluate disease mechanisms and potential treatment strategies for diabetes.…”

Section: Introductionmentioning

confidence: 99%

“…This mechanism may be attributed to the inhibition of the NF-kB pathway, limiting the release of pro-inflammatory cytokines and reducing lipid peroxidation in the heart of diabetic animals. 19 In addition, EGCG has strong antioxidant activity, which can prevent or T2DM and complications by scavenging oxygen-free radicals and improving OS. Myung-Kwan Han's study revealed that EGCG can combat IL-1β-induced RINm5F cell apoptosis.…”

Section: Introductionmentioning

confidence: 99%

EGCG Upregulates UCP3 Levels to Protect MIN6 Pancreatic Islet Cells from Interleukin-1β-Induced Apoptosis

Jia

Luo

Gao

et al. 2020

DDDT

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The protective effects of epigallocatechin gallate (EGCG) on interleukin-1β (IL-1β)-induced apoptosis were investigated in murine MIN 6 pancreatic β-cells. The role of uncoupling protein-3 (UCP 3) signaling in this process was also explored. Methods: After treatment with IL-1β and EGCG, cells were collected and analyzed. Cell viability was measured using the CCK 8 assay and the function of β-cells was evaluated by analyzing insulin secretion. Detection of mitochondrial function in cells was performed by measuring mitochondrial membrane potential, the concentration of ATP and activity of ROS. Apoptosis was analyzed by Hochest33258 staining and flow cytometry. Expression levels of UCP 3 were interrogated using immunohistochemistry, RT-PCR and Western blotting. Results: Compared with the control group, IL-1β treatment (20nM) for 24 h significantly decreased cell viability and insulin secretion, damaged mitochondrial function and increased ROS activity. Results also showed increased apoptosis and a decrease in UCP 3 expression levels (p<0.01). However, treatment with low (1mM) or high (5mM) concentrations of EGCG significantly decreased IL-1β-induced apoptosis (p<0.01), restored mitochondrial function and subsequently increased UCP 3 levels in IL-1β-induced β-cells (p<0.01). Conclusion: These results suggest that EGCG protects against IL-1β-induced mitochondrial injury and apoptosis in β-cells through the up-regulation of UCP 3 .

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JNK1/2 regulates ER–mitochondrial Ca²⁺ cross-talk during IL-1β–mediated cell death in RINm5F and human primary β-cells

Cited by 26 publications

References 57 publications

Decoding the oxidative stress hypothesis in diabetic embryopathy through proapoptotic kinase signaling

Decoding the oxidative stress hypothesis in diabetic embryopathy through proapoptotic kinase signaling

Mitochondrial metabolism directs stemness and differentiation in P19 embryonal carcinoma stem cells

<p>EGCG Upregulates UCP<sub>3</sub> Levels to Protect MIN<sub>6</sub> Pancreatic Islet Cells from Interleukin-1β-Induced Apoptosis</p>

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