Mitochondria to plasma membrane redox signaling is essential for fatty acid β-oxidation-driven insulin secretion

• Published in: Redox biology 2024-09, Vol.75, p.103283, Article 103283
• Main Authors: Jabůrek, Martin, Klöppel, Eduardo, Průchová, Pavla, Mozheitova, Oleksandra, Tauber, Jan, Engstová, Hana, Ježek, Petr
• Format: Article
• Language: English
• Subjects: Animals; Cell Membrane - metabolism; Fatty acid-stimulated insulin secretion; Fatty Acids - metabolism; Glucose - metabolism; GPR40; Group VI Phospholipases A2 - genetics; Group VI Phospholipases A2 - metabolism; Hydrogen Peroxide - metabolism; Insulin - metabolism; Insulin Secretion; Insulin-Secreting Cells - metabolism; Mice; Mice, Knockout; Mitochondria - metabolism; Mitochondrial fatty acids; Oxidation-Reduction; Pancreatic β-cells; Receptors, G-Protein-Coupled; Redox signaling; Redox-activated phospholipase iPLA2γ; Research Paper; Signal Transduction
• ISSN: 2213-2317; 2213-2317
• DOI: 10.1016/j.redox.2024.103283

We asked whether acute redox signaling from mitochondria exists concomitantly to fatty acid- (FA-) stimulated insulin secretion (FASIS) at low glucose by pancreatic β-cells. We show that FA β-oxidation produces superoxide/H2O2, providing: i) mitochondria-to-plasma-membrane redox signaling, closing KATP-channels synergically with elevated ATP (substituting NADPH-oxidase-4-mediated H2O2-signaling upon glucose-stimulated insulin secretion); ii) activation of redox-sensitive phospholipase iPLA2γ/PNPLA8, cleaving mitochondrial FAs, enabling metabotropic GPR40 receptors to amplify insulin secretion (IS). At fasting glucose, palmitic acid stimulated IS in wt mice; palmitic, stearic, lauric, oleic, linoleic, and hexanoic acids also in perifused pancreatic islets (PIs), with suppressed 1st phases in iPLA2γ/PNPLA8-knockout mice/PIs. Extracellular/cytosolic H2O2-monitoring indicated knockout-independent redox signals, blocked by mitochondrial antioxidant SkQ1, etomoxir, CPT1 silencing, and catalase overexpression, all inhibiting FASIS, keeping ATP-sensitive K+-channels open, and diminishing cytosolic [Ca2+]-oscillations. FASIS in mice was a postprandially delayed physiological event. Redox signals of FA β-oxidation are thus documented, reaching the plasma membrane, essentially co-stimulating IS. [Display omitted] •Fatty acids stimulate insulin secretion at low glucose in pancreatic islet β-cells.•Mitochondrial β-oxidation of fatty acids provides redox signal for insulin secretion.•Pancreatic islets release H2O2 upon insulin fatty acid-stimulated insulin secretion.•Redox-activated mitochondrial phospholipase iPLA2γ supplies fatty acids for GPR40.•Insulin is secreted up to 6 h after administration of Intralipid to mice.