Fink 2022 FASEB Bioadv
Fink BD, Rauckhorst AJ, Taylor EB, Yu L, Sivitz WI (2022) Membrane potential-dependent regulation of mitochondrial complex II by oxaloacetate in interscapular brown adipose tissue. FASEB Bioadv 4:197-210. https://doi.org/10.1096/fba.2021-00137 |
Fink BD, Rauckhorst AJ, Taylor EB, Yu L, Sivitz WI (2022) FASEB Bioadv
Abstract: Classically, mitochondrial respiration responds to decreased membrane potential (ΞΞ¨) by increasing respiration. However, we found that for succinate-energized complex II respiration in skeletal muscle mitochondria (unencumbered by rotenone), low ΞΞ¨ 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 ΞΞ¨ 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 ΞΞ¨, 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 ΞΞ¨ but also increased rather than decreased (as classically predicted under low ΞΞ¨) O2 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 ΞΞ¨ 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 ΞΞ¨ 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 ΞΞ¨ altering substrate flow through OAA and OAA inhibition of SDH.
β’ Bioblast editor: Gnaiger E β’ O2k-Network Lab: US IA Iowa City Sivitz WI
Labels: MiParea: Respiration
Tissue;cell: Fat Preparation: Isolated mitochondria
Regulation: Inhibitor, mt-Membrane potential
Pathway: S HRR: Oxygraph-2k, TPP