Membrane potential-dependent regulation of mitochondrial complex II by oxaloacetate in interscapular brown adipose tissue.

Autor: Fink BD; Department of Internal Medicine/Endocrinology and Metabolism University of Iowa and the Iowa City Veterans Affairs Medical Center Iowa City Iowa USA., Rauckhorst AJ; Department of Molecular Physiology and Biophysics University of Iowa Iowa City Iowa USA., Taylor EB; Department of Molecular Physiology and Biophysics University of Iowa Iowa City Iowa USA., Yu L; Department of Biochemistry and Molecular Biology University of Iowa Iowa City Iowa USA.; NMR Core Facility University of Iowa Iowa City Iowa USA., Sivitz WI; Department of Internal Medicine/Endocrinology and Metabolism University of Iowa and the Iowa City Veterans Affairs Medical Center Iowa City Iowa USA.
Jazyk: angličtina
Zdroj: FASEB bioAdvances [FASEB Bioadv] 2021 Dec 03; Vol. 4 (3), pp. 197-210. Date of Electronic Publication: 2021 Dec 03 (Print Publication: 2022).
DOI: 10.1096/fba.2021-00137
Abstrakt: Classically, mitochondrial respiration responds to decreased membrane potential (ΔΨ) by increasing respiration. However, we found that for succinate-energized complex II respiration in skeletal muscle mitochondria (unencumbered by rotenone), low ΔΨ impairs respiration by a mechanism culminating in oxaloacetate (OAA) inhibition of succinate dehydrogenase (SDH). Here, we investigated whether this phenomenon extends to far different mitochondria of a tissue wherein ΔΨ is intrinsically low, i.e., interscapular brown adipose tissue (IBAT). Also, to advance our knowledge of the mechanism, we performed isotopomer studies of metabolite flux not done in our previous muscle studies. In additional novel work, we addressed possible ways ADP might affect the mechanism in IBAT mitochondria. UCP1 activity, and consequently ΔΨ, were perturbed both by GDP, a well-recognized potent inhibitor of UCP1 and by the chemical uncoupler carbonyl cyanide m-chlorophenyl hydrazone (FCCP). In succinate-energized mitochondria, GDP increased ΔΨ but also increased rather than decreased (as classically predicted under low ΔΨ) O 2  flux. In GDP-treated mitochondria, FCCP reduced potential but also decreased respiration. Metabolite studies by NMR and flux analyses by LC-MS support a mechanism, wherein ΔΨ effects on the production of reactive oxygen alters the NADH/NAD + ratio affecting OAA accumulation and, hence, OAA inhibition of SDH. We also found that ADP-altered complex II respiration in complex fashion probably involving decreased ΔΨ due to ATP synthesis, a GDP-like nucleotide inhibition of UCP1, and allosteric enzyme action. In summary, complex II respiration in IBAT mitochondria is regulated by UCP1-dependent ΔΨ altering substrate flow through OAA and OAA inhibition of SDH.
Competing Interests: The authors declare that they have no conflicts of interest with the contents of this article.
(© 2021 The Authors. FASEB BioAdvances published by Wiley Periodicals LLC on behalf of The Federation of American Societies for Experimental Biology.)
Databáze: MEDLINE
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