Journal Article

The proapoptotic BH3-only proteins Bim and Puma are downstream of endoplasmic reticulum and mitochondrial oxidative stress in pancreatic islets in response to glucotoxicity

Rondas, D, Kay, T W H, Fynch, S, Overbergh, L, Wali, J A, Gurzov, E N, McKenzie, M D, Akira, S, Strasser, A, Thomas, H E, Mathieu, C, Zhao, Y, Elkerbout, L

2014

Overview

Apoptosis of pancreatic beta cells is a feature of type 2 diabetes and its prevention may have therapeutic benefit. High glucose concentrations induce apoptosis of islet cells, and this requires the proapoptotic Bcl-2 homology domain 3 (BH3)-only proteins Bim and Puma. We studied the stress pathways induced by glucotoxicity in beta cells that result in apoptosis. High concentrations of glucose or ribose increased expression of the transcription factor CHOP (C/EBP homologous protein) but not endoplasmic reticulum (ER) chaperones, indicating activation of proapoptotic ER stress signaling. Inhibition of ER stress prevented ribose-induced upregulation of Chop and Puma mRNA, and partially protected islets from glucotoxicity. Loss of Bim or Puma partially protected islets from the canonical ER stressor thapsigargin. The antioxidant N -acetyl-cysteine also partially protected islets from glucotoxicity. Islets deficient in both Bim and Puma, but not Bim or Puma alone, were significantly protected from killing induced by the mitochondrial reactive oxygen species donor rotenone. Our data demonstrate that high concentrations of glucose induce ER and oxidative stress, which causes cell death mediated by Bim and Puma. We observed significantly higher Bim and Puma mRNA in islets of human donors with type 2 diabetes. This indicates that inhibition of Bim and Puma, or their inducers, may prevent beta-cell destruction in type 2 diabetes.

• Publisher: Nature Publishing Group UK,Springer Nature B.V,Nature Publishing Group
• Subject: 631/80/82/23 / 631/80/86 / 692/698/1460/1583 / 692/699/2743/137/773 / Animals / Antibodies / Antioxidants - pharmacology / Apoptosis - drug effects / Apoptosis Regulatory Proteins - deficiency / Apoptosis Regulatory Proteins - genetics / Apoptosis Regulatory Proteins - metabolism / Bcl-2-Like Protein 11 / Biochemistry / Biomedical and Life Sciences / Cell Biology / Cell Culture / Cell Line / Diabetes Mellitus, Type 2 - metabolism / Diabetes Mellitus, Type 2 - pathology / Endoplasmic Reticulum - drug effects / Endoplasmic Reticulum - metabolism / Endoplasmic Reticulum - pathology / Endoplasmic Reticulum Stress - drug effects / Glucose - metabolism / Humans / Immunology / Insulin-Secreting Cells - metabolism / Insulin-Secreting Cells - pathology / Islets of Langerhans - drug effects / Islets of Langerhans - metabolism / Islets of Langerhans - pathology / Life Sciences / Membrane Proteins - deficiency / Membrane Proteins - genetics / Membrane Proteins - metabolism / Mice / Mice, 129 Strain / Mice, Inbred C57BL / Mice, Knockout / Mitochondria - drug effects / Mitochondria - metabolism / Mitochondria - pathology / Original / original-article / Oxidants - pharmacology / Oxidative Stress - drug effects / Proto-Oncogene Proteins - deficiency / Proto-Oncogene Proteins - genetics / Proto-Oncogene Proteins - metabolism / Ribose - metabolism / RNA, Messenger - metabolism / Tissue Culture Techniques / Transcription Factor CHOP - deficiency / Transcription Factor CHOP - genetics / Tumor Suppressor Proteins - deficiency / Tumor Suppressor Proteins - genetics / Tumor Suppressor Proteins - metabolism