Mitochondrial Carriers Regulating Insulin Secretion Profiled in Human Islets upon Metabolic Stress

Jiménez‐Sánchez, Cecilia; Brun, Thierry; Maechler, Pierre

doi:10.3390/biom10111543

Cited by 12 publications

(6 citation statements)

References 94 publications

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“…This overactivity at low glucose resulted in blunted OXPHOS/ATP responses to high glucose (Figure 2), and accumulation of both PPP intermediates and glycerol-3-phosphate (Chareyron et al, 2020). Another study on human islets in culture similarly found that hyperglycemia/ glucotoxicity (3 days; 25 mM glucose) initially increased the expression of mitochondrial carriers, ETC components, and mitochondrial import machinery (Jimenez-Sanchez et al, 2020). Direct effects of inhibiting mitochondrial pyruvate metabolism using 10 μM UK5099 rescued the metabolic defects and glucose induced Ca 2+ influx, supporting a theory that enhanced early mitochondrial metabolism contributes to islet dysfunction in hyperglycemia (Chareyron et al, 2020).…”

Section: Mitochondrial Metabolism and Bioenergetics In Gluco-and Lipo...mentioning

confidence: 89%

Mitochondrial bioenergetics, metabolism, and beyond in pancreatic β-cells and diabetes

Rivera Nieves,

Wauford,

2024

Front. Mol. Biosci.

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In Type 1 and Type 2 diabetes, pancreatic β-cell survival and function are impaired. Additional etiologies of diabetes include dysfunction in insulin-sensing hepatic, muscle, and adipose tissues as well as immune cells. An important determinant of metabolic health across these various tissues is mitochondria function and structure. This review focuses on the role of mitochondria in diabetes pathogenesis, with a specific emphasis on pancreatic β-cells. These dynamic organelles are obligate for β-cell survival, function, replication, insulin production, and control over insulin release. Therefore, it is not surprising that mitochondria are severely defective in diabetic contexts. Mitochondrial dysfunction poses challenges to assess in cause-effect studies, prompting us to assemble and deliberate the evidence for mitochondria dysfunction as a cause or consequence of diabetes. Understanding the precise molecular mechanisms underlying mitochondrial dysfunction in diabetes and identifying therapeutic strategies to restore mitochondrial homeostasis and enhance β-cell function are active and expanding areas of research. In summary, this review examines the multidimensional role of mitochondria in diabetes, focusing on pancreatic β-cells and highlighting the significance of mitochondrial metabolism, bioenergetics, calcium, dynamics, and mitophagy in the pathophysiology of diabetes. We describe the effects of diabetes-related gluco/lipotoxic, oxidative and inflammation stress on β-cell mitochondria, as well as the role played by mitochondria on the pathologic outcomes of these stress paradigms. By examining these aspects, we provide updated insights and highlight areas where further research is required for a deeper molecular understanding of the role of mitochondria in β-cells and diabetes.

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Section: Mitochondrial Metabolism and Bioenergetics In Gluco-and Lipo...mentioning

confidence: 89%

Mitochondrial bioenergetics, metabolism, and beyond in pancreatic β-cells and diabetes

Rivera Nieves,

Wauford,

2024

Front. Mol. Biosci.

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“…This study also concluded that, through the bioinformatic analysis, NDUFS8 might be a potential therapeutic target, which needed further studies together with molecular experiments [114]. During the formation of T2DM, high glucose, as a strong metabolic stressor, also induced the upregulation of NDUFS8 [115]. Additionally, NDUFS8 exhibited increased interaction with insulin receptor substrate 1, which was linked to inflammation-mediated insulin resistance in T2DM patients [116].…”

Section: Ndufs8 and Diabetes Mellitusmentioning

confidence: 93%

Emerging Roles of NDUFS8 Located in Mitochondrial Complex I in Different Diseases

et al. 2022

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NADH:ubiquinone oxidoreductase core subunit S8 (NDUFS8) is an essential core subunit and component of the iron-sulfur (FeS) fragment of mitochondrial complex I directly involved in the electron transfer process and energy metabolism. Pathogenic variants of the NDUFS8 are relevant to infantile-onset and severe diseases, including Leigh syndrome, cancer, and diabetes mellitus. With over 1000 nuclear genes potentially causing a mitochondrial disorder, the current diagnostic approach requires targeted molecular analysis, guided by a combination of clinical and biochemical features. Currently, there are only several studies on pathogenic variants of the NDUFS8 in Leigh syndrome, and a lack of literature on its precise mechanism in cancer and diabetes mellitus exists. Therefore, NDUFS8-related diseases should be extensively explored and precisely diagnosed at the molecular level with the application of next-generation sequencing technologies. A more distinct comprehension will be needed to shed light on NDUFS8 and its related diseases for further research. In this review, a comprehensive summary of the current knowledge about NDUFS8 structural function, its pathogenic mutations in Leigh syndrome, as well as its underlying roles in cancer and diabetes mellitus is provided, offering potential pathogenesis, progress, and therapeutic target of different diseases. We also put forward some problems and solutions for the following investigations.

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“…Note also that metabolic pathways including metabolic shuttles are plastic, specifically when the key members are altered in their expression, such as identified upon glucotoxicity, lipotoxicity, and glucolipotoxicity in isolated human PIs ( 108 ). Therefore, the description below concerns with the most frequent schemes before and after glucose intake into intact pancreatic β-cells.…”

Section: Mitochondrial Metabolism Of Pancreatic β-Cellsmentioning

confidence: 99%

Contribution of Mitochondria to Insulin Secretion by Various Secretagogues

Ježek

Holendová

Jabůrek

et al. 2022

Antioxidants & Redox Signaling

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Significance: Mitochondria determine glucose-stimulated insulin secretion (GSIS) in pancreatic b-cells by elevating ATP synthesis. As the metabolic and redox hub, mitochondria provide numerous links to the plasma membrane channels, insulin granule vesicles (IGVs), cell redox, NADH, NADPH, and Ca 2+ homeostasis, all affecting insulin secretion. Recent Advances: Mitochondrial redox signaling was implicated in several modes of insulin secretion (branched-chain ketoacid [BCKA]-, fatty acid [FA]-stimulated). Mitochondrial Ca 2+ influx was found to enhance GSIS, reflecting cytosolic Ca 2+ oscillations induced by action potential spikes (intermittent opening of voltage-dependent Ca 2+ and K + channels) or the superimposed Ca 2+ release from the endoplasmic reticulum (ER). The ATPase inhibitory factor 1 (IF1) was reported to tune the glucose sensitivity range for GSIS. Mitochondrial protein kinase A was implicated in preventing the IF1-mediated inhibition of the ATP synthase. Critical Issues: It is unknown how the redox signal spreads up to the plasma membrane and what its targets are, what the differences in metabolic, redox, NADH/NADPH, and Ca 2+ signaling, and homeostasis are between the first and second GSIS phase, and whether mitochondria can replace ER in the amplification of IGV exocytosis. Future Directions: Metabolomics studies performed to distinguish between the mitochondrial matrix and cytosolic metabolites will elucidate further details. Identifying the targets of cell signaling into mitochondria and of mitochondrial retrograde metabolic and redox signals to the cell will uncover further molecular mechanisms for insulin secretion stimulated by glucose, BCKAs, and FAs, and the amplification of secretion by glucagon-like peptide (GLP-1) and metabotropic receptors. They will identify the distinction between the hub b-cells and their followers in intact and diabetic states. Antioxid. Redox Signal. 00, 000-000.

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Mitochondrial Carriers Regulating Insulin Secretion Profiled in Human Islets upon Metabolic Stress

Cited by 12 publications

References 94 publications

Mitochondrial bioenergetics, metabolism, and beyond in pancreatic β-cells and diabetes

Mitochondrial bioenergetics, metabolism, and beyond in pancreatic β-cells and diabetes

Emerging Roles of NDUFS8 Located in Mitochondrial Complex I in Different Diseases

Contribution of Mitochondria to Insulin Secretion by Various Secretagogues

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