Q-Flux: A method to assess hepatic mitochondrial succinate dehydrogenase, methylmalonyl-CoA mutase, and glutaminase fluxes in vivo.

Autor: Hubbard BT; Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06510, USA; Department of Cellular & Molecular Physiology, Yale School of Medicine, New Haven, CT 06510, USA., LaMoia TE; Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06510, USA; Department of Cellular & Molecular Physiology, Yale School of Medicine, New Haven, CT 06510, USA., Goedeke L; Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06510, USA., Gaspar RC; Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06510, USA., Galsgaard KD; Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06510, USA., Kahn M; Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06510, USA., Mason GF; Department of Radiology & Biomedical Imaging, Yale School of Medicine, New Haven, CT 06510, USA; Departments of Psychiatry & Biomedical Engineering, Yale School of Medicine, New Haven, CT 06510, USA., Shulman GI; Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06510, USA; Department of Cellular & Molecular Physiology, Yale School of Medicine, New Haven, CT 06510, USA. Electronic address: gerald.shulman@yale.edu.
Jazyk: angličtina
Zdroj: Cell metabolism [Cell Metab] 2023 Jan 03; Vol. 35 (1), pp. 212-226.e4. Date of Electronic Publication: 2022 Dec 13.
DOI: 10.1016/j.cmet.2022.11.011
Abstrakt: The mammalian succinate dehydrogenase (SDH) complex has recently been shown as capable of operating bidirectionally. Here, we develop a method (Q-Flux) capable of measuring absolute rates of both forward (V SDH(F) ) and reverse (V SDH(R) ) flux through SDH in vivo while also deconvoluting the amount of glucose derived from four discreet carbon sources in the liver. In validation studies, a mitochondrial uncoupler increased net SDH flux by >100% in awake rodents but also increased SDH cycling. During hyperglucagonemia, attenuated pyruvate cycling enhances phosphoenolpyruvate carboxykinase efficiency to drive increased gluconeogenesis, which is complemented by increased glutaminase (GLS) flux, methylmalonyl-CoA mutase (MUT) flux, and glycerol conversion to glucose. During hyperinsulinemic-euglycemic clamp, both pyruvate carboxylase and GLS are suppressed, while V SDH(R) is increased. Unstimulated MUT is a minor anaplerotic reaction but is readily induced by small amounts of propionate, which elicits glucagon-like metabolic rewiring. Taken together, Q-Flux yields a comprehensive picture of hepatic mitochondrial metabolism and should be broadly useful to researchers.
Competing Interests: Declaration of interests The authors declare no competing interests.
(Copyright © 2022 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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