Diluted serum from calorie-restricted animals promotes mitochondrial β-cell adaptations and protect against glucolipotoxicity
Fernanda M. Cerqueira,Fernanda M. Cerqueira,Fernanda M. Cerqueira,Bruno Chausse,Boris M. Baranovski,Marc Liesa,Marc Liesa,Eli C. Lewis,Orian S. Shirihai,Orian S. Shirihai,Orian S. Shirihai,Alicia J. Kowaltowski +11 more
TLDR
Evidence is provided that non‐nutrient factors in serum have a major impact on β‐cell mitochondrial adaptations to changes in metabolism, as indicated by CR‐mediated prevention of mitochondrial fusion arrest and reduced respiratory function in INS1 cells under glucolipotoxicity.Abstract:
β-cells quickly adjust insulin secretion to oscillations in nutrients carried by the blood, acting as fuel sensors. However, most studies of β-cell responses to nutrients do not discriminate between fuel levels and signaling components present in the circulation. Here we studied the effect of serum from calorie-restricted rats versus serum from rats fed ad libitum, diluted tenfold in the medium, which did not contribute significantly to the pool of nutrients, on β-cell mitochondrial function and dynamics under regular and high-nutrient culture conditions. Insulin secreting beta-cell derived line (INS1) cells incubated with serum from calorie-restricted rats (CR serum) showed higher levels of peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC-1α) and active nitric oxide synthase. The expression of mitofusin-2 (Mfn-2) and optic atrophy 1 (OPA-1), proteins involved in mitochondrial fusion, was increased, while the levels of the mitochondrial fission mediator dynamin related protein 1 (DRP-1) were reduced. Consistent with changes in mitochondrial dynamics protein levels, CR serum treatment increased mitochondrial fusion rates, as well as their length and connectivity. These changes in mitochondrial morphology were associated with prolonged glucose-stimulated insulin secretion and mitochondrial respiration. When combining CR serum and high levels of glucose and palmitate (20 and 0.4 mm, respectively), an in vitro model of type II diabetes, we observed that signaling promoted by CR serum was enough to overcome glucolipotoxicity, as indicated by CR-mediated prevention of mitochondrial fusion arrest and reduced respiratory function in INS1 cells under glucolipotoxicity. Overall, our results provide evidence that non-nutrient factors in serum have a major impact on β-cell mitochondrial adaptations to changes in metabolism.read more
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Mitochondrial dynamics in type 2 diabetes: Pathophysiological implications
Susana Rovira-Llopis,Celia Bañuls,Noelia Diaz-Morales,Antonio Hernández-Mijares,Milagros Rocha,Victor M. Victor +5 more
TL;DR: The molecular pathways of mitochondria dynamics, their impairment under type 2 diabetes, and pharmaceutical approaches for targeting mitochondrial dynamics, such as mitochondrial division inhibitor-1 (mdivi-1), dynasore, P110 and 15-oxospiramilactone are discussed.
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Mitochondrial Dynamics and Mitochondrial Dysfunction in Diabetes
Jun Wada,Atsuko Nakatsuka +1 more
TL;DR: The molecular mechanism of mitochondrial dynamics, its abnormality in diabetes and obesity, and pharmaceuticals targeting mitochondrial biogenesis, fission, fusion and mitophagy are described.
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Cell culture models of fatty acid overload: Problems and solutions
TL;DR: This review discusses lipotoxicity models, the potential problems encountered when using these cellular models, as well as practical solutions for difficulties encountered.
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Nutrient-Induced Metabolic Stress, Adaptation, Detoxification, and Toxicity in the Pancreatic β-Cell.
TL;DR: This work addresses the gluco-, lipo-, and glucolipo-toxicities in β-cells by assessing the evidence both for and against each of them and proposes that a more general term should be used for the in vivo situation of overweight-associated type 2 diabetes reflecting both the adaptive and toxic processes to mixed calorigenic nutrients excess: “nutrient-induced metabolic stress” or, in brief, ”nutri-stress.
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Mitochondrial morphology regulates organellar Ca2+ uptake and changes cellular Ca2+ homeostasis
Alicia J. Kowaltowski,Sergio L. Menezes-Filho,Essam A. Assali,Isabela G. Gonçalves,João Victor Cabral-Costa,Phablo Abreu,Nathanael Miller,Patricia Nolasco,Francisco R.M. Laurindo,Alexandre Bruni-Cardoso,Orian S. Shirihai +10 more
TL;DR: Modulating mitochondrial dynamics toward increased fusion through expression of a dominant negative form of the fission protein markedly increased both mitochondrialCa2+ retention capacity and Ca2+ uptake rates in permeabilized C2C12 cells, showing a novel role for mitochondrial morphology in the regulation of mitochondrial Ca2- uptake, which impacts cellular Ca2+, homeostasis.
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