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

Genetic screens have been used extensively to probe interactions between nuclear genes and their impact on phenotypes. Probing interactions between mitochondrial genes and their phenotypic outcome, however, has not been possible due to a lack of tools to map the responsible polymorphisms. Here, using a toolkit we previously established in Drosophila, we isolate over 300 recombinant mitochondrial genomes and map a naturally occurring polymorphism at the cytochrome c oxidase III residue 109 (CoIII109) that fully rescues the lethality and other defects associated with a point mutation in cytochrome c oxidase I (CoIT300I). Through lipidomics profiling, biochemical assays and phenotypic analyses, we show that the CoIII109 polymorphism modulates cardiolipin binding to prevent complex IV instability caused by the CoIT300I mutation. This study demonstrates the feasibility of genetic interaction screens in animal mitochondrial DNA. It unwraps the complex intra-genomic interplays underlying disorders linked to mitochondrial DNA and how they influence disease expression.

• MeSH
• Drosophila genetics   MeSH
• Cardiolipins * genetics   metabolism   MeSH
• DNA, Mitochondrial * genetics   metabolism   MeSH
• Mitochondria genetics   metabolism   MeSH
• Electron Transport Complex IV metabolism   MeSH
• Synthetic Lethal Mutations MeSH
• Animals MeSH
• Check Tag
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Cardiolipins * MeSH
• DNA, Mitochondrial * MeSH
• Electron Transport Complex IV MeSH

Significance: Mitochondrial (mt) reticulum network in the cell possesses amazing ultramorphology of parallel lamellar cristae, formed by the invaginated inner mitochondrial membrane. Its non-invaginated part, the inner boundary membrane (IBM) forms a cylindrical sandwich with the outer mitochondrial membrane (OMM). Crista membranes (CMs) meet IBM at crista junctions (CJs) of mt cristae organizing system (MICOS) complexes connected to OMM sorting and assembly machinery (SAM). Cristae dimensions, shape, and CJs have characteristic patterns for different metabolic regimes, physiological and pathological situations. Recent Advances: Cristae-shaping proteins were characterized, namely rows of ATP-synthase dimers forming the crista lamella edges, MICOS subunits, optic atrophy 1 (OPA1) isoforms and mitochondrial genome maintenance 1 (MGM1) filaments, prohibitins, and others. Detailed cristae ultramorphology changes were imaged by focused-ion beam/scanning electron microscopy. Dynamics of crista lamellae and mobile CJs were demonstrated by nanoscopy in living cells. With tBID-induced apoptosis a single entirely fused cristae reticulum was observed in a mitochondrial spheroid. Critical Issues: The mobility and composition of MICOS, OPA1, and ATP-synthase dimeric rows regulated by post-translational modifications might be exclusively responsible for cristae morphology changes, but ion fluxes across CM and resulting osmotic forces might be also involved. Inevitably, cristae ultramorphology should reflect also mitochondrial redox homeostasis, but details are unknown. Disordered cristae typically reflect higher superoxide formation. Future Directions: To link redox homeostasis to cristae ultramorphology and define markers, recent progress will help in uncovering mechanisms involved in proton-coupled electron transfer via the respiratory chain and in regulation of cristae architecture, leading to structural determination of superoxide formation sites and cristae ultramorphology changes in diseases. Antioxid. Redox Signal. 39, 635-683.

• Keywords
• ATP-synthase dimeric rows, MICOS, OPA1, mitochondrial cristae, mitochondrial superoxide formation, respiratory chain supercomplexes,
• MeSH
• Adenosine Triphosphate metabolism   MeSH
• Homeostasis MeSH
• Mitochondrial Membranes * metabolism   MeSH
• Mitochondrial Proteins metabolism   MeSH
• Oxidation-Reduction MeSH
• Superoxides * metabolism   MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH
• Names of Substances
• Adenosine Triphosphate MeSH
• Mitochondrial Proteins MeSH
• Superoxides * MeSH