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Open AccessArticle

Flavin Adenine Dinucleotide Fluorescence as an Early Marker of Mitochondrial Impairment During Brain Hypoxia

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Institute for Imaging Science and Computational Modelling in Cardiovascular Medicine Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, 10117 Berlin, Germany
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Institute for Neurophysiology, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, 10117 Berlin, Germany
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Neuroscience Research Center, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, 10117 Berlin, Germany
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Institute of Biochemistry, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, 10117 Berlin, Germany
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Center for Stroke Research Berlin, Center for Stroke Research Berlin, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany
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Department of Neurology, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany
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Department of Experimental Neurology, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany
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Bernstein Center for Computational Neuroscience Berlin, 10117 Berlin, Germany
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Einstein Center for Neurosciences Berlin, 10117 Berlin, Germany
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Berlin Institute of Health, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, 10117 Berlin, Germany
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Department of Anesthesiology and Intensive Care, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, 10117 Berlin, Germany
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(11), 3977; https://doi.org/10.3390/ijms21113977
Received: 2 May 2020 / Revised: 28 May 2020 / Accepted: 30 May 2020 / Published: 1 June 2020
(This article belongs to the Special Issue Flavin Adenine Dinucleotide (FAD): Biosynthesis and Function)
Multimodal continuous bedside monitoring is increasingly recognized as a promising option for early treatment stratification in patients at risk for ischemia during neurocritical care. Modalities used at present are, for example, oxygen availability and subdural electrocorticography. The assessment of mitochondrial function could be an interesting complement to these modalities. For instance, flavin adenine dinucleotide (FAD) fluorescence permits direct insight into the mitochondrial redox state. Therefore, we explored the possibility of using FAD fluorometry to monitor consequences of hypoxia in brain tissue in vitro and in vivo. By combining experimental results with computational modeling, we identified the potential source responsible for the fluorescence signal and gained insight into the hypoxia-associated metabolic changes in neuronal energy metabolism. In vitro, hypoxia was characterized by a reductive shift of FAD, impairment of synaptic transmission and increasing interstitial potassium [K+]o. Computer simulations predicted FAD changes to originate from the citric acid cycle enzyme α-ketoglutarate dehydrogenase and pyruvate dehydrogenase. In vivo, the FAD signal during early hypoxia displayed a reductive shift followed by a short oxidation associated with terminal spreading depolarization. In silico, initial tissue hypoxia followed by a transient re-oxygenation phase due to glucose depletion might explain FAD dynamics in vivo. Our work suggests that FAD fluorescence could be readily used to monitor mitochondrial function during hypoxia and represents a potential diagnostic tool to differentiate underlying metabolic processes for complementation of multimodal brain monitoring. View Full-Text
Keywords: FAD; brain; hypoxia; spreading depolarization; mitochondria; computational modeling FAD; brain; hypoxia; spreading depolarization; mitochondria; computational modeling
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Berndt, N.; Kovács, R.; Rösner, J.; Wallach, I.; Dreier, J.P.; Liotta, A. Flavin Adenine Dinucleotide Fluorescence as an Early Marker of Mitochondrial Impairment During Brain Hypoxia. Int. J. Mol. Sci. 2020, 21, 3977.

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