Main Article Content
Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by impaired glucose homeostasis, insulin resistance, and beta cell dysfunction. Emerging evidence suggests that the mitochondrial electron transport chain (ETC) plays a pivotal role in regulating beta cell function and glucose homeostasis. Antimycin A is a known inhibitor of the mitochondrial ETC complex III, which could potentially impact beta cell metabolism and function. In this study, we aimed to investigate the effect of antimycin A on beta cell metabolism using a metabolomics-based LC-MS approach. Murine pancreatic beta cells (MIN 6) were treated with antimycin A (1 µM) for 2 hr. Control cells were treated with glucose. Metabolites were extracted from the cells, and LC-MS analysis was performed using a high-resolution mass spectrometer. Metabolic profiling was performed using the MetaboAnalyst 5.0. Metabolites were identified and quantified using a metabolite library. Statistical analysis was performed using multivariate and univariate approaches. Metabolic profiling of antimycin A -treated beta cells revealed significant alterations in cellular metabolism compared to control cells. The most significant changes were observed in the metabolism of amino acid, nucleotides, and the tricarboxylic acid (TCA) cycle. Antimycin A can affect these, possibly leading to insulin secretion impairment. The results of this study highlight the potential of antimycin A as a valuable tool for exploring the impact of mitochondrial function on beta cell metabolism and function. The observed changes in metabolite profiles in antimycin A-treated cells shed light on the metabolic pathways crucial for beta cell function and may offer valuable insights for the development of novel diabetes therapies. The metabolomics analysis conducted using LC-MS in this study represents a powerful approach for investigating the consequences of mitochondrial dysfunction on cellular metabolism.
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
Upon acceptance of an article, the Pharmacological and Therapeutic Society of Thailand will have exclusive right to publish and distribute the article in all forms and media and grant rights to others. Authors have rights to use and share their own published articles.
Nolfi-Donegan D, Braganza A, Shiva S. Mitochondrial electron transport chain: Oxidative phosphorylation, oxidant production, and methods of measurement. Redox Biol. 2020;37:101674.
Hytti M, Korhonen E, Hyttinen JMT, Roehrich H, Kaarniranta K, Ferrington DA, Kauppinen A. Antimycin A-induced mitochondrial damage causes human RPE cell death despite activation of autophagy. Oxid Med Cell Longev. 2019;2019:1583656.
Ma X, Jin M, Cai Y, Xia H, Long K, Liu J, et al. Mitochondrial electron transport chain complex III is required for antimycin A to inhibit autophagy. Chem Biol. 2011;18(11):1474-1481.
Bauermeister A, Mannochio-Russo H, Costa-Lotufo LV, Jarmusch AK, Dorrestein PC. Mass spectrometry-based metabolomics in micro-biome investigations. Nat Rev Microbiol. 2022;20(3):143-160.
Muthubharathi BC, Gowripriya T, Balamurugan K. Metabolomics: small molecules that matter more. Mol Omics. 2021;17(2):210-229.
Rinschen MM, Ivanisevic J, Giera M, Siuzdak G. Identification of bioactive metabolites using activity metabolomics. Nat Rev Mol Cell Biol. 2019;20(6):353-367.
Reveglia P, Paolillo C, Ferretti G, Carlo AD, Angiolillo A, Nasso R, et al. Challenges in LC-MS-based metabolomics for Alzheimer's disease early detection: targeted approaches versus untargeted approaches. Metabolomics. 2021;17(9):78.
Dator R, Villalta PW, Thomson N, Jensen J, Hatsukami DK, Stepanov I, et al. Metabolomics profiles of smokers from two ethnic groups with differing lung cancer risk. Chem Res Toxicol. 2020;33(8):2087-2098.
Muelas MW, Roberts I, Mughal F, O'Hagan S, Day PJ, Kell DB. An untargeted metabolomics strategy to measure differences in metabolite uptake and excretion by mammalian cell lines. Metabolomics. 2020;16(10):107.
Danzi F, Pacchiana R, Mafficini A, Scupoli MT, Scarpa A, Donadelli M, et al. To metabolomics and beyond: a technological portfolio to investigate cancer metabolism. Sig Transduct Target Ther. 2023;8(137):1-22.
Alarcon-Barrera JC, Kostidis S, Ondo-Mendez A, Giera M. Recent advances in metabolomics analysis for early drug development. Drug Discov Today. 2022; 27(6):1763-1773.
van der Walt G, Lindeque JZ, Mason S, Louw R. Sub-cellular metabolomics contributes mitochondria-specific metabolic insights to a mouse model of Leigh syndrome. Metabolites. 2021;11(10):658.
Cataldo LR, Cortés VA, Mizgier ML, Aranda E, Mezzano D, Olmos P, et al. Fluoxetine impairs insulin secretion without modifying extracellular serotonin levels in MIN6 β-cells. Exp Clin Endocrinol Diabetes. 2015;123(8):473-478.
Ngamratanapaiboon S, Yambangyang P. Quantification of antipsychotic biotransformation in brain microvascular endothelial cells by using untargeted metabolomics. Drug Discov Ther. 2021;15(6):317-324.
Pizarro-Delgado J, Deeney JT, Corkey BE, Tamarit-Rodriguez J. Direct stimulation of islet insulin secretion by glycolytic and mitochondrial metabolites in KCl-depolarized islets. PLoS One.2016;11(11):e0166111.
Marek CB, Peralta RM, Itinose AM, Bracht A. Influence of tamoxifen on gluconeogenesis and glycolysis in the perfused rat liver. Chem Biol Interact. 2011;193(1):22-33.
Al-Mass A, Poursharifi P, Peyot ML, Lussier R, Levens EJ, Guida J, et al. Glycerol-3-phosphate phosphatase operates a glycerol shunt in pancreatic β-cells that controls insulin secretion and metabolic stress. Mol Metab. 2022;60:101471.
Possik E, Al-Mass A, Peyot ML, Ahmad R, Al-Mulla F, Madiraju SRM, et al. New mammalian glycerol-3-phosphate phosphatase: role in β-Cell, liver and adipocyte metabolism. Front Endocrinol (Lausanne). 2021;12:706607.
Swierczynski J, Zabrocka L, Goyke E, Raczynska S, Adamonis W, Sledzinski Z. Enhanced glycerol 3-phosphate dehydrogenase activity in adipose tissue of obese humans. Mol Cell Biochem. 2003;254(1-2):55-59.
Bonora M, Patergnani S, Rimessi A, Marchi ED, Suski JM, Bononi A, et al. ATP synthesis and storage. Purinergic Signal. 2012;8(3):343-357.
Fridlyand LE, Jacobson DA, Philipson LH. Ion channels and regulation of insulin secretion in human β-cells: a computational systems analysis. Islets. 2013;5(1):1-15.
Duvoor C, Dendi VS, Marco A, Shekhawat NS, Chada A, Ravilla R, Musham CK, et al. Commentary: ATP: The crucial component of secretory vesicles: accelerated ATP/insulin exocytosis and prediabetes. Front Physiol. 2017;8:53.
Li J, Yan H, Xiang R, Yang W, Ye J, Yin R, et al. ATP secretion and metabolism in regulating pancreatic beta cell functions and hepatic glycolipid metabolism. Front Physiol. 2022;13:918042.
Judge A, Dodd MS. Metabolism. Essays Biochem. 2020;64(4):607-647.
Martínez-Reyes I, Chandel NS. Mitochondrial TCA cycle metabolites control physiology and disease. Nat Commun. 2020;11(1):102.
Chakrabarty RP, Chandel NS. Mitochondria as signaling organelles control mammalian stem cell fate. Cell Stem Cell. 2021;28(3): 394-408.
Newsholme P, Krause M. Nutritional regulation of insulin secretion: implications for diabetes. Clin Biochem Rev. 2012;33(2):35-47.
Fu Z, Gilbert ER, Liu D. Regulation of insulin synthesis and secretion and pancreatic Beta-cell dysfunction in diabetes. Curr Diabetes Rev. 2013;9(1):25-53.