caa a22 4500 445324899 CHVBK 20180317142717.0 cr unu---uuuuu 170323e20110401xx s 000 0 eng 10.1007/s10858-011-9482-8 doi (NATIONALLICENCE)springer-10.1007/s10858-011-9482-8 Metabolic profiles show specific mitochondrial toxicities in vitro in myotube cells [Elektronische Daten] [Qiuwei Xu, Heather Vu, Liping Liu, Ting-Chuan Wang, William Schaefer] Mitochondrial toxicity has been a serious concern, not only in preclinical drug development but also in clinical trials. In mitochondria, there are several distinct metabolic processes including fatty acid β-oxidation, the tricarboxylic acid (TCA) cycle, and oxidative phosphorylation (OXPHOS), and each process contains discrete but often intimately linked steps. Interruption in any one of those steps can cause mitochondrial dysfunction. Detection of inhibition to OXPHOS can be complicated in vivo because intermediate endogenous metabolites can be recycled in situ or circulated systemically for metabolism in other organs or tissues. Commonly used assays for evaluating mitochondrial function are often applied to ex vivo or in vitro samples; they include various enzymatic or protein assays, as well as functional assays such as measurement of oxygen consumption rate, membrane potential, or acidification rates. Metabolomics provides quantitative profiles of overall metabolic changes that can aid in the unraveling of explicit biochemical details of mitochondrial inhibition while providing a holistic view and heuristic understanding of cellular bioenergetics. In this paper, we showed the application of quantitative NMR metabolomics to in vitro myotube cells treated with mitochondrial toxicants, rotenone and antimycin A. The close coupling of the TCA cycle to the electron transfer chain (ETC) in OXPHOS enables specific diagnoses of inhibition to ETC complexes by discrete biochemical changes in the TCA cycle. Springer Science+Business Media B.V., 2011 NMR nationallicence Mitochondria nationallicence Toxicity nationallicence Metabolomics nationallicence NMR : Nuclear magnetic resonance nationallicence FID : Free induction decay nationallicence WET : Water suppression enhanced through T1 effects nationallicence DSS-d6 : 2,2-dimethyl-2-silapentane-5-sulfonate sodium, or sodium 3-(trimethylsilyl)-1-propanesulfonate nationallicence DMSO : Dimethyl sulfoxide nationallicence LC-MS : Liquid chromatography-mass spectrometer nationallicence MRS : Magnetic resonance spectroscopy nationallicence TCA : Tricarboxylic acid nationallicence ETC : Electron transfer chain nationallicence PCr : Phosphocreatine nationallicence ATP : Adenosine triphosphate nationallicence ADP : Adenosine diphosphate nationallicence NADH : Reduced nicotinamide adenine dinucleotide nationallicence NAD+ : Nicotinamide adenine dinucleotide nationallicence FADH2 : Reduced flavin adenine dinucleotide nationallicence FAD+ : Flavin adenine dinucleotide nationallicence CoQ or Q : Coenzyme Q, or ubiquinone nationallicence CoQH2 : Ubiquinol nationallicence OXPHOS : Oxidative phosphorylation nationallicence OCR : Oxygen consumption rate nationallicence ECAR : Extracellular acidification rate nationallicence MPT : Mitochondrial permeability transition nationallicence LDH : Lactate dehydrogenase nationallicence Xu Qiuwei Merck Research Laboratories, 770 Sumneytown Pike, 19486, West Point, PA, USA aut Vu Heather Merck Research Laboratories, 770 Sumneytown Pike, 19486, West Point, PA, USA aut Liu Liping Merck Research Laboratories, 770 Sumneytown Pike, 19486, West Point, PA, USA aut Wang Ting-Chuan Merck Research Laboratories, 126 E. Lincoln Avenue, 07065, Rahway, NJ, USA aut Schaefer William Merck Research Laboratories, 770 Sumneytown Pike, 19486, West Point, PA, USA aut Journal of Biomolecular NMR Springer Netherlands 49/3-4(2011-04-01), 207-219 0925-2738 49:3-4<207 2011 49 10858 https://doi.org/10.1007/s10858-011-9482-8 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s10858-011-9482-8 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Xu Qiuwei Merck Research Laboratories, 770 Sumneytown Pike, 19486, West Point, PA, USA aut NATIONALLICENCE 700 1- Vu Heather Merck Research Laboratories, 770 Sumneytown Pike, 19486, West Point, PA, USA aut NATIONALLICENCE 700 1- Liu Liping Merck Research Laboratories, 770 Sumneytown Pike, 19486, West Point, PA, USA aut NATIONALLICENCE 700 1- Wang Ting-Chuan Merck Research Laboratories, 126 E. Lincoln Avenue, 07065, Rahway, NJ, USA aut NATIONALLICENCE 700 1- Schaefer William Merck Research Laboratories, 770 Sumneytown Pike, 19486, West Point, PA, USA aut NATIONALLICENCE 773 0- Journal of Biomolecular NMR Springer Netherlands 49/3-4(2011-04-01), 207-219 0925-2738 49:3-4<207 2011 49 10858 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer