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

» PMID: 35392250 Open Access

Fink BD, Rauckhorst AJ, Taylor EB, Yu L, Sivitz WI (2022) FASEB Bioadv

Abstract: 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) 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 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.

• Bioblast editor: Gnaiger E • 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