ArticleAntioxidants & redox signaling2015
H₂O₂-Activated Mitochondrial Phospholipase iPLA₂γ Prevents Lipotoxic Oxidative Stress in Synergy with UCP2, Amplifies Signaling via G-Protein-Coupled Receptor GPR40, and Regulates Insulin Secretion in Pancreatic β-Cells.
Article in Antioxidants & redox signaling, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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33 citing papers in PubMed, 49 citations in OpenAlex.
- A Function-Centric Framework for Mitochondrial Quality Control.Biomolecules · 2026Review
- Manganese Superoxide Dismutase: Structure, Function, and Implications in Human Disease.Antioxidants (Basel, Switzerland) · 2025Review
- Mitochondrial uncoupling protein 2: a central player in pancreatic disease pathophysiology.Molecular medicine (Cambridge, Mass.) · 2024Review
- Mitochondrial Physiology of Cellular Redox Regulations.Physiological research · 2024Review
- Mitochondrial Cristae Morphology Reflecting Metabolism, Superoxide Formation, Redox Homeostasis, and Pathology.Antioxidants & redox signaling · 2023Review
- Pitfalls of Mitochondrial Redox Signaling Research.Antioxidants (Basel, Switzerland) · 2023Review
- Mitochondrial Peroxiredoxin 3 Is Rapidly Oxidized and Hyperoxidized by Fatty Acid Hydroperoxides.Antioxidants (Basel, Switzerland) · 2023Article
- Adipose Tissue Secretion Pattern Influences β-Cell Wellness in the Transition from Obesity to Type 2 Diabetes.International journal of molecular sciences · 2022Review
- Contribution of Mitochondria to Insulin Secretion by Various Secretagogues.Antioxidants & redox signaling · 2022Review
- Antioxidant Role and Cardiolipin Remodeling by Redox-Activated Mitochondrial CaAntioxidants (Basel, Switzerland) · 2022Article
- Preparation of fatty acid solutions exerts significant impact on experimental outcomes in cell culture models of lipotoxicity.Biology methods & protocols · 2022Article
- Antioxidant Synergy of Mitochondrial Phospholipase PNPLA8/iPLA2γ with Fatty Acid-Conducting SLC25 Gene Family Transporters.Antioxidants (Basel, Switzerland) · 2021Review
- Redox Homeostasis in Pancreatic β-Cells: From Development to Failure.Antioxidants (Basel, Switzerland) · 2021Review
- Transcriptional Regulation of ROS Homeostasis by the ERR Subfamily of Nuclear Receptors.Antioxidants (Basel, Switzerland) · 2021Review
- Mitochondria exert age-divergent effects on recovery from spinal cord injury.Experimental neurology · 2021Article
- Lipotoxic Impairment of Mitochondrial Function in β-Cells: A Review.Antioxidants (Basel, Switzerland) · 2021Review
- The Pancreatic β-Cell: The Perfect Redox System.Antioxidants (Basel, Switzerland) · 2021Review
- Mitochondrial Superoxide Production Decreases on Glucose-Stimulated Insulin Secretion in Pancreatic β Cells Due to Decreasing Mitochondrial Matrix NADH/NADAntioxidants & redox signaling · 2020Article
- Glucose-Induced Expression of DAPIT in Pancreatic β-Cells.Biomolecules · 2020Article
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5 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
aimsPancreatic β-cell chronic lipotoxicity evolves from acute free fatty acid (FA)-mediated oxidative stress, unprotected by antioxidant mechanisms. Since mitochondrial uncoupling protein-2 (UCP2) plays antioxidant and insulin-regulating roles in pancreatic β-cells, we tested our hypothesis, that UCP2-mediated uncoupling attenuating mitochondrial superoxide production is initiated by FA release due to a direct H2O2-induced activation of mitochondrial phospholipase iPLA2γ.
resultsPro-oxidant tert-butylhydroperoxide increased respiration, decreased membrane potential and mitochondrial matrix superoxide release rates of control but not UCP2- or iPLA2γ-silenced INS-1E cells. iPLA2γ/UCP2-mediated uncoupling was alternatively activated by an H2O2 burst, resulting from palmitic acid (PA) β-oxidation, and it was prevented by antioxidants or catalase overexpression. Exclusively, nascent FAs that cleaved off phospholipids by iPLA2γ were capable of activating UCP2, indicating that the previously reported direct redox UCP2 activation is actually indirect. Glucose-stimulated insulin release was not affected by UCP2 or iPLA2γ silencing, unless pro-oxidant activation had taken place. PA augmented insulin secretion via G-protein-coupled receptor 40 (GPR40), stimulated by iPLA2γ-cleaved FAs (absent after GPR40 silencing). INNOVATION AND
conclusionThe iPLA2γ/UCP2 synergy provides a feedback antioxidant mechanism preventing oxidative stress by physiological FA intake in pancreatic β-cells, regulating glucose-, FA-, and redox-stimulated insulin secretion. iPLA2γ is regulated by exogenous FA via β-oxidation causing H2O2 signaling, while FAs are cleaved off phospholipids, subsequently acting as amplifying messengers for GPR40. Hence, iPLA2γ acts in eminent physiological redox signaling, the impairment of which results in the lack of antilipotoxic defense and contributes to chronic lipotoxicity.
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