Journal article
Membrane potential-dependent regulation of mitochondrial complex II by oxaloacetate in interscapular brown adipose tissue
FASEB bioAdvances, Vol.4(3), pp.197-210
03/01/2022
DOI: 10.1096/fba.2021-00137
PMCID: PMC8973305
PMID: 35392250
Abstract
Classically, mitochondrial respiration responds to decreased membrane potential (Delta psi) by increasing respiration. However, we found that for succinate-energized complex II respiration in skeletal muscle mitochondria (unencumbered by rotenone), low Delta psi 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 Delta psi 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 Delta psi, 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 Delta psi but also increased rather than decreased (as classically predicted under low Delta psi) 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 Delta psi 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 Delta psi 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 Delta psi altering substrate flow through OAA and OAA inhibition of SDH.
Details
- Title: Subtitle
- Membrane potential-dependent regulation of mitochondrial complex II by oxaloacetate in interscapular brown adipose tissue
- Creators
- Brian D. Fink - Department of Internal Medicine/Endocrinology and MetabolismAdam J. Rauckhorst - Univ Iowa, Dept Mol Physiol & Biophys, Iowa City, IA USAEric B. Taylor - Department of Molecular Physiology and BiophysicsLiping Yu - University of IowaWilliam I. Sivitz - Department of Internal Medicine/Endocrinology and Metabolism
- Resource Type
- Journal article
- Publication Details
- FASEB bioAdvances, Vol.4(3), pp.197-210
- DOI
- 10.1096/fba.2021-00137
- PMID
- 35392250
- PMCID
- PMC8973305
- NLM abbreviation
- FASEB Bioadv
- ISSN
- 2573-9832
- eISSN
- 2573-9832
- Publisher
- Wiley
- Number of pages
- 14
- Grant note
- Iowa Fraternal Order of the Eagles R01 DK123043--01A1 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA I01 BX000285--06 / U.S. Department of Veterans Affairs; US Department of Veterans Affairs
- Language
- English
- Date published
- 03/01/2022
- Academic Unit
- Molecular Physiology and Biophysics; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Medicine Administration; Endocrinology and Metabolism; Internal Medicine
- Record Identifier
- 9984297606702771
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