Chronic oxidative stress, which is caused by aberrant non-receptor tyrosine kinase
(c-Abl) signaling, plays a key role in the progression of β-cell loss in diabetes
mellitus. Recent studies, however, have linked ferroptotic-like death to the β-cell
loss in diabetes mellitus. Here, we report that oxidative stress-driven reduced/oxidized
glutathione (GSH/GSSG) loss and proteasomal degradation of glutathione peroxidase
4 (GPX4) promote ferroptotic-like cell damage through increased lipid peroxidation.
Mechanistically, treatment with GNF2, a non-ATP competitive c-Abl kinase inhibitor,
selectively preserves β-cell function by inducing the orphan nuclear receptor estrogen-related
receptor gamma (ERRγ). ERRγ-driven glutaminase 1 (GLS1) expression promotes the elevation of the GSH/GSSG ratio, and this increase leads
to the inhibition of lipid peroxidation by GPX4. Strikingly, pharmacological inhibition
of ERRγ represses the expression of GLS1 and reverses the GSH/GSSG ratio linked to mitochondrial dysfunction and increased
lipid peroxidation mediated by GPX4 degradation. Inhibition of GLS1 suppresses the ERRγ agonist DY131-induced GSH/GSSG ratio linked to ferroptotic-like
death owing to the loss of GPX4. Furthermore, immunohistochemical analysis showed
enhanced ERRγ and GPX4 expression in the pancreatic islets of GNF2-treated mice compared
to that in streptozotocin-treated mice. Altogether, our results provide the first
evidence that the orphan nuclear receptor ERRγ-induced GLS1 expression augments the glutathione antioxidant system, and its downstream signaling
leads to improved β-cell function and survival under oxidative stress conditions.
Abbreviations:
ERRγ (Estrogen-related receptor gamma), GLS1 (Glutaminase 1), GSH (Glutathione)To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Translational ResearchAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Mechanisms of pancreatic beta-cell death in type 1 and type 2 diabetes: many differences, few similarities.Diabetes. 2005; 54 (Suppl): S97-S107
- Chemistry and biology of reactive species with special reference to the antioxidative defence status in pancreatic β-cells.Biochim Biophys Acta Gen Subj. 2017; 1861: 1929-1942
- A choice of death–the signal-transduction of immune-mediated beta-cell apoptosis.Diabetologia. 2001; 44: 2115-2133
- Oxidative stress: the vulnerable beta-cell.Biochem Soc Trans. 2008; 36 (Pt 3): 343-347
- beta-Cell death during progression to diabetes.Nature. 2001; 414: 792-798
- Non-receptor tyrosine kinase inhibitors enhances β-cell survival by suppressing the PKCδ signal transduction pathway in streptozotocin-induced β-cell apoptosis.Cell Signal. 2015; 27: 1066-1074
- Protein kinase PKC delta and c-Abl are required for mitochondrial apoptosis induction by genotoxic stress in the absence of p53, p73 and Fas receptor.FEBS Lett. 2006; 580: 2547-2552
- The PKCdelta-Abl complex communicates ER stress to the mitochondria - an essential step in subsequent apoptosis.J Cell Sci. 2008; 121 (Pt 6): 804-813
- Inhibition of protein kinase C delta protects rat INS-1 cells against interleukin-1beta and streptozotocin-induced apoptosis.Diabetes. 2002; 51: 317-324
- Cycling, stressed-out and nervous: cellular functions of c-Abl.Trends Cell Biol. 1999; 9: 179-186
- Tyrosine 311 is phosphorylated by c-Abl and promotes the apoptotic effect of PKCdelta in glioma cells.Biochem Biophys Res Commun. 2007; 352: 431-436
- Low antioxidant enzyme gene expression in pancreatic islets compared with various other mouse tissues.Free Radic Biol Med. 1996; 20: 463-466
- Redox environment of the cell as viewed through the redox state of the glutathione disulfide/glutathione couple.Free Radic Biol Med. 2001; 30: 1191-1212
- Ferroptosis: an iron-dependent form of nonapoptotic cell death.Cell. 2012; 149: 1060-1072
- Ferroptosis: a regulated cell death nexus linking metabolism, redox biology, and disease.Cell. 2017; 171: 273-285
- Ferroptosis-inducing agents compromise in vitro human islet viability and function.Cell Death Dis. 2018; 9: 595
- Regulation of ferroptotic cancer cell death by GPX4.Cell. 2014; 156: 317-331
- Genome-wide orchestration of cardiac functions by the orphan nuclear receptors ERR alpha and gamma.Cell Metab. 2007; 5: 345-356
- Estrogen related receptors (ERRs): a new dawn in transcriptional control of mitochondrial gene networks.Mitochondrion. 2011; 11: 544-552
- Transcriptional control of energy homeostasis by the estrogen-related receptors.Endocr Rev. 2008; 29: 677-696
- Transcriptional regulation of ROS homeostasis by the ERR subfamily of nuclear receptors.Antioxidants (Basel). 2021; 10: 437
- Impaired myogenesis in estrogen-related receptor γ (ERRγ)-deficient skeletal myocytes due to oxidative stress.FASEB J. 2013; 27: 135-150
- Estrogen-related receptors are targetable ROS sensors.Genes Dev. 2020; 34: 544-559
- ERRgamma directs and maintains the transition to oxidative metabolism in the postnatal heart.Cell Metab. 2007; 6: 13-24
- ERRγ is required for the metabolic maturation of therapeutically functional glucose-responsive β cells.Cell Metab. 2016; 23: 622-634
- Hydroxyl radical formation in diabetic rats induced by streptozotocin.Life Sci. 1995; 56: 1789-1798
- Streptozocin- and alloxan-induced H2O2 generation and DNA fragmentation in pancreatic islets. H2O2 as mediator for DNA fragmentation.Diabetes. 1991; 40: 1141-1145
- Generation of hydrogen peroxide and failure of antioxidative responses in pancreatic islets of male C57BL/6 mice are associated with diabetes induced by multiple low doses of streptozotocin.Diabetologia. 2004; 47: 676-685
- Glucose toxicity in beta-cells: type 2 diabetes, good radicals gone bad, and the glutathione connection.Diabetes. 2003; 52: 581-587
- The cystine/cysteine cycle: a redox cycle regulating susceptibility versus resistance to cell death.Oncogene. 2008; 27: 1618-1628
- Glucose-independent glutamine metabolism via TCA cycling for proliferation and survival in B cells.Cell Metab. 2012; 15: 110-121
- Glutamine regulates expression of key transcription factor, signal transduction, metabolic gene, and protein expression in a clonal pancreatic beta-cell line.J Endocrinol. 2006; 190: 719-727
- Glutamate acts as a key signal linking glucose metabolism to incretin/cAMP action to amplify insulin secretion.Cell Rep. 2014; 9: 661-673
- β-Cell glutamate signaling: Its role in incretin-induced insulin secretion.J Diabetes Investig. 2016; 7 (Suppl 1(Suppl): 38-43
- Tyrosine kinase inhibitors and diabetes: a novel treatment paradigm?.Trends Endocrinol Metab. 2015; 26: 643-656
- c-Abl inhibition mitigates diet-induced obesity through improving insulin sensitivity of subcutaneous fat in mice.Diabetologia. 2017; 60: 900-910
- Targeting ABL-IRE1α signaling spares ER-stressed pancreatic β cells to reverse autoimmune diabetes.Cell Metab. 2017; 25 (e8): 883-897
- Regulation of phagocyte NADPH oxidase by hydrogen peroxide through a Ca (2+)/c-Abl signaling pathway.Free Radic Biol Med. 2010; 48: 798-810
- Quantitative redox biology: an approach to understand the role of reactive species in defining the cellular redox environment.Cell Biochem Biophys. 2013; 67: 477-483
- Oestrogen-related receptors in breast cancer: control of cellular metabolism and beyond.Nat Rev Cancer. 2013; 13: 27-36
- A TAZ-ANGPTL4-NOX2 axis regulates ferroptotic cell death and chemoresistance in epithelial ovarian cancer.Mol Cancer Res. 2020; 18: 79-90
- NOX2 deficiency protects against streptozotocin-induced beta-cell destruction and development of diabetes in mice.Diabetes. 2010; 59: 2603-2611
- Glutamine reliance in cell metabolism.Exp Mol Med. 2020; 52: 1496-1516
- Purification and characterization of phospholipid hydroperoxide glutathione peroxidase from rat testis mitochondrial membranes.Biochim Biophys Acta. 1994; 1208: 211-221
- Glutathione peroxidase 4-catalyzed reduction of lipid hydroperoxides in membranes: The polar head of membrane phospholipids binds the enzyme and addresses the fatty acid hydroperoxide group toward the redox center.Free Radic Biol Med. 2017; 112: 1-11
- Estrogen-related receptor γ serves a role in blood pressure homeostasis during pregnancy.Mol Endocrinol. 2014; 28: 965-975
- Glutamate is an essential mediator in glutamine-amplified insulin secretion.J Diabetes Investig. 2021; 12: 920-930
- Preserving insulin secretion in diabetes by inhibiting VDAC1 overexpression and surface translocation in β cells.Cell Metab. 2019; 29 (e6): 64-77
- Carbonylation contributes to SERCA2a activity loss and diastolic dysfunction in a rat model of type 1 diabetes.Diabetes. 2011; 60: 947-959
- Ca (2+)-mediated regulation of VDAC1 expression levels is associated with cell death induction.Biochim Biophys Acta. 2014; 1843: 2270-2281
- Glutamate interacts with VDAC and modulates opening of the mitochondrial permeability transition pore.J Bioenerg Biomembr. 2004; 36: 179-186
Article info
Publication history
Published online: June 10, 2022
Accepted:
June 6,
2022
Received in revised form:
May 12,
2022
Received:
December 25,
2021
Identification
Copyright
© 2022 Elsevier Inc. All rights reserved.
