Journal article
Oxaloacetate regulates complex II respiration in brown fat: dependence on UCP1 expression
American Journal of Physiology: Cell Physiology, Vol.324(6), pp.C1236-C1248
06/01/2023
DOI: 10.1152/ajpcell.00565.2022
PMCID: PMC10243537
PMID: 37125774
Abstract
We previously found that skeletal muscle mitochondria incubated at low membrane potential (AT) or interscapular brown adi-pose tissue (IBAT) mitochondria, wherein AT is intrinsically low, accumulate oxaloacetate (OAA) in amounts sufficient to inhibit complex II respiration. We proposed a mechanism wherein low AT reduces reverse electron transport (RET) to complex I caus-ing a low NADH/NAD thorn ratio favoring malate conversion to OAA. To further assess the mechanism and its physiologic relevance, we carried out studies of mice with inherently different levels of IBAT mitochondrial inner membrane potential. Isolated complex II (succinate)-energized IBAT mitochondria from obesity-resistant 129SVE mice compared with obesity-prone C57BL/6J displayed greater UCP1 expression, similar O2 flux despite lower AT, similar OAA concentrations, and similar NADH/NAD thorn . When GDP was added to inhibit UCP1, 129SVE IBAT mitochondria, despite their lower AT, exhibited much lower respiration, twofold greater OAA concentrations, much lower RET (as marked by ROS), and much lower NADH and NADH/NAD thorn ratios compared with the C57BL/6J IBAT mitochondria. UCP1 knock-out abolished OAA accumulation by succinate-energized mitochondria associated with markedly greater AT, ROS, and NADH, but equal or greater O2 flux compared with WT mitochondria. GDP addition, com-pared with no GDP, increased AT and complex II respiration in wild-type (WT) mice associated with much less OAA. Respiration on complex I substrates followed the more classical dynamics of greater respiration at lower AT. These findings support the abovementioned mechanism for OAA-and AT-dependent complex II respiration and support its physiological relevance.NEW & NOTEWORTHY We examined mitochondrial respiration initiated at mitochondrial complex II in mice with varying degrees of brown adipose tissue UCP1 expression. We show that, by affecting inner membrane potential, UCP1 expression determines reverse electron transport from complex II to complex I and, consequently, the NADH/NAD thorn ratio. Accordingly, this regulates the level of oxaloacetate accumulation and the extent of oxaloacetate inhibition of complex II
Details
- Title: Subtitle
- Oxaloacetate regulates complex II respiration in brown fat: dependence on UCP1 expression
- Creators
- Ritu Som - University of Iowa, Internal MedicineBrian D. Fink - University of Iowa, Internal MedicineLiping Yu - University of Iowa, Medicine AdministrationWilliam I. Sivitz - University of Iowa, Endocrinology and Metabolism
- Resource Type
- Journal article
- Publication Details
- American Journal of Physiology: Cell Physiology, Vol.324(6), pp.C1236-C1248
- Publisher
- Amer Physiological Soc
- DOI
- 10.1152/ajpcell.00565.2022
- PMID
- 37125774
- PMCID
- PMC10243537
- ISSN
- 0363-6143
- eISSN
- 1522-1563
- Number of pages
- 13
- Grant note
- DOI: 10.13039/100002069, name: Iowa Fraternal Order of the Eagles; DOI: 10.13039/100017618, name: HHS | NIH | NIDDK | Division of Diabetes, Endocrinology, and Metabolic Diseases, award: 1 R01 DK123043-01A1; DOI: 10.13039/100007496, name: Biomedical Laboratory Research and Development, VA Office of Research and Development, award: I01 BX000285-06
- Language
- English
- Date published
- 06/01/2023
- Academic Unit
- Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Medicine Administration; Endocrinology and Metabolism; Internal Medicine
- Record Identifier
- 9984473217402771
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