Oxaloacetate regulates complex II respiration in brown fat: dependence on UCP1 expression

• Published in: American Journal of Physiology: Cell Physiology Vol. 324; no. 6; p. C1236
• Main Authors: Som, Ritu, Fink, Brian D, Yu, Liping, Sivitz, William I
• Format: Journal Article
• Language: English
• Published: United States 01-06-2023
• Subjects: Adipose Tissue, Brown - metabolism; Animals; Electron Transport Complex I - genetics; Electron Transport Complex I - metabolism; Membrane Potential, Mitochondrial; Mice; Mice, Inbred C57BL; NAD - metabolism; Obesity - metabolism; Oxaloacetic Acid - metabolism; Oxaloacetic Acid - pharmacology; Reactive Oxygen Species - metabolism; Respiration; Succinates - metabolism; Uncoupling Protein 1 - genetics; Uncoupling Protein 1 - metabolism; mitochondrial complex II; brown adipose tissue; mitochondria; oxaloacetate; succinate dehydrogenase
• ISSN: 1522-1563
• DOI: 10.1152/ajpcell.00565.2022

We previously found that skeletal muscle mitochondria incubated at low membrane potential (ΔΨ) or interscapular brown adipose tissue (IBAT) mitochondria, wherein ΔΨ is intrinsically low, accumulate oxaloacetate (OAA) in amounts sufficient to inhibit complex II respiration. We proposed a mechanism wherein low ΔΨ reduces reverse electron transport (RET) to complex I causing a low NADH/NAD
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 O
flux despite lower ΔΨ, similar OAA concentrations, and similar NADH/NAD
. When GDP was added to inhibit UCP1, 129SVE IBAT mitochondria, despite their lower ΔΨ, exhibited much lower respiration, twofold greater OAA concentrations, much lower RET (as marked by ROS), and much lower NADH and NADH/NAD
ratios compared with the C57BL/6J IBAT mitochondria. UCP1 knock-out abolished OAA accumulation by succinate-energized mitochondria associated with markedly greater ΔΨ, ROS, and NADH, but equal or greater O
flux compared with WT mitochondria. GDP addition, compared with no GDP, increased ΔΨ 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 ΔΨ. These findings support the abovementioned mechanism for OAA- and ΔΨ-dependent complex II respiration and support its physiological relevance.
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
ratio. Accordingly, this regulates the level of oxaloacetate accumulation and the extent of oxaloacetate inhibition of complex II.