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.

• Keywords
• Fatty acid-stimulated insulin secretion, GPR40, Mitochondrial fatty acids, Pancreatic β-cells, Redox signaling, Redox-activated phospholipase iPLA2γ,
• MeSH
• Insulin-Secreting Cells * metabolism   MeSH
• Cell Membrane * metabolism   MeSH
• Group VI Phospholipases A2 metabolism   genetics   MeSH
• Glucose metabolism   MeSH
• Insulin metabolism   MeSH
• Fatty Acids * metabolism   MeSH
• Mitochondria * metabolism   MeSH
• Mice, Knockout MeSH
• Mice MeSH
• Oxidation-Reduction * MeSH
• Hydrogen Peroxide metabolism   MeSH
• Receptors, G-Protein-Coupled MeSH
• Insulin Secretion * MeSH
• Signal Transduction * MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Ffar1 protein, mouse MeSH Browser
• Group VI Phospholipases A2 MeSH
• Glucose MeSH
• Insulin MeSH
• Fatty Acids * MeSH
• Hydrogen Peroxide MeSH
• Pla2g6 protein, mouse MeSH Browser
• Receptors, G-Protein-Coupled MeSH

Mitochondria (mt) represent the vital hub of the molecular physiology of the cell, being decision-makers in cell life/death and information signaling, including major redox regulations and redox signaling. Now we review recent advances in understanding mitochondrial redox homeostasis, including superoxide sources and H2O2 consumers, i.e., antioxidant mechanisms, as well as exemplar situations of physiological redox signaling, including the intramitochondrial one and mt-to-cytosol redox signals, which may be classified as acute and long-term signals. This review exemplifies the acute redox signals in hypoxic cell adaptation and upon insulin secretion in pancreatic beta-cells. We also show how metabolic changes under these circumstances are linked to mitochondrial cristae narrowing at higher intensity of ATP synthesis. Also, we will discuss major redox buffers, namely the peroxiredoxin system, which may also promote redox signaling. We will point out that pathological thresholds exist, specific for each cell type, above which the superoxide sources exceed regular antioxidant capacity and the concomitant harmful processes of oxidative stress subsequently initiate etiology of numerous diseases. The redox signaling may be impaired when sunk in such excessive pro-oxidative state.

• MeSH
• Antioxidants metabolism   MeSH
• Insulin-Secreting Cells metabolism   MeSH
• Humans MeSH
• Mitochondria * metabolism   MeSH
• Oxidation-Reduction * MeSH
• Oxidative Stress physiology   MeSH
• Signal Transduction physiology   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Antioxidants MeSH