Mitochondrial Carriers Regulating Insulin Secretion Profiled in Human Islets upon Metabolic Stress
Open Access
- 12 November 2020
- journal article
- research article
- Published by MDPI AG in Biomolecules
- Vol. 10 (11), 1543
- https://doi.org/10.3390/biom10111543
Abstract
Chronic exposure of β-cells to nutrient-rich metabolic stress impairs mitochondrial metabolism and its coupling to insulin secretion. We exposed isolated human islets to different metabolic stresses for 3 days: 0.4 mM oleate or 0.4 mM palmitate at physiological 5.5 mM glucose (lipotoxicity), high 25 mM glucose (glucotoxicity), and high 25 mM glucose combined with 0.4 mM oleate and/or palmitate (glucolipotoxicity). Then, we profiled the mitochondrial carriers and associated genes with RNA-Seq. Diabetogenic conditions, and in particular glucotoxicity, increased expression of several mitochondrial solute carriers in human islets, such as the malate carrier DIC, the α-ketoglutarate-malate exchanger OGC, and the glutamate carrier GC1. Glucotoxicity also induced a general upregulation of the electron transport chain machinery, while palmitate largely counteracted this effect. Expression of different components of the TOM/TIM mitochondrial protein import system was increased by glucotoxicity, whereas glucolipotoxicity strongly upregulated its receptor subunit TOM70. Expression of the mitochondrial calcium uniporter MCU was essentially preserved by metabolic stresses. However, glucotoxicity altered expression of regulatory elements of calcium influx as well as the Na+/Ca2+ exchanger NCLX, which mediates calcium efflux. Overall, the expression profile of mitochondrial carriers and associated genes was modified by the different metabolic stresses exhibiting nutrient-specific signatures.Keywords
Funding Information
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (#166625)
- Bo & Kerstin Hjelt Diabetes Foundation (CJS)
- Fundación Alfonso Martín Escudero (CJS)
This publication has 95 references indexed in Scilit:
- Frequency-dependent mitochondrial Ca2+ accumulation regulates ATP synthesis in pancreatic β cellsPflügers Archiv - European Journal of Physiology, 2012
- Mitochondrial Ca2+ Uptake 1 (MICU1) and Mitochondrial Ca2+ Uniporter (MCU) Contribute to Metabolism-Secretion Coupling in Clonal Pancreatic β-CellsJournal of Biological Chemistry, 2012
- Body iron stores and risk of type 2 diabetes: results from the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam studyDiabetologia, 2012
- A Common Variant in TFB1M Is Associated with Reduced Insulin Secretion and Increased Future Risk of Type 2 DiabetesCell Metabolism, 2011
- Frataxin and Mitochondrial FeS Cluster BiogenesisOnline Journal of Public Health Informatics, 2010
- Mitochondrial iron trafficking and the integration of iron metabolism between the mitochondrion and cytosolProceedings of the National Academy of Sciences of the United States of America, 2010
- NCLX is an essential component of mitochondrial Na + /Ca 2+ exchangeProceedings of the National Academy of Sciences of the United States of America, 2009
- Mitochondrial Glutamate Carrier GC1 as a Newly Identified Player in the Control of Glucose-stimulated Insulin SecretionOnline Journal of Public Health Informatics, 2009
- Discovery of Genes Essential for Heme Biosynthesis through Large-Scale Gene Expression AnalysisCell Metabolism, 2009
- The role of iron in type 2 diabetes in humansBiochimica et Biophysica Acta (BBA) - General Subjects, 2009