Fink 2019 FASEB J

Fink BD, Yu L, Sivitz WI (2019) Modulation of complex II-energized respiration in muscle, heart, and brown adipose mitochondria by oxaloacetate and complex I electron flow. FASEB J [Epub ahead of print].

» PMID: 31361970

Fink BD, Yu L, Sivitz WI (2019) FASEB J

Abstract: We recently reported that membrane potential (ΔΨ) primarily determines the relationship of complex II-supported respiration by isolated skeletal muscle mitochondria to ADP concentrations. We observed that O2 flux peaked at low ADP concentration ([ADP]) (high ΔΨ) before declining at higher [ADP] (low ΔΨ). The decline resulted from oxaloacetate (OAA) accumulation and inhibition of succinate dehydrogenase. This prompted us to question the effect of incremental [ADP] on respiration in interscapular brown adipose tissue (IBAT) mitochondria, wherein ΔΨ is intrinsically low because of uncoupling protein 1 (UCP1). We found that succinate-energized IBAT mitochondria, even in the absence of ADP, accumulate OAA and manifest limited respiration, similar to muscle mitochondria at high [ADP]. This could be prevented by guanosine 5'-diphosphate inhibition of UCP1. NAD⁺ cycling with NADH requires complex I electron flow and is needed to form OAA. Therefore, to assess the role of electron transit, we perturbed flow using a small molecule, N1-(3-acetamidophenyl)-N2-(2-(4-methyl-2-(p-tolyl)thiazol-5-yl)ethyl)oxalamide. We observed decreased OAA, increased NADH/NAD⁺, and increased succinate-supported mitochondrial respiration under conditions of low ΔΨ (IBAT) but not high ΔΨ (heart). In summary, complex II-energized respiration in IBAT mitochondria is tempered by complex I-derived OAA in a manner dependent on UCP1. These dynamics depend on electron transit in complex I. • Keywords: S1QEL 1.1, Brown adipose tissue, Mitochondrial respiratory chain, Succinate dehydrogenase • Bioblast editor: Plangger M • O2k-Network Lab: US IA Iowa City Sivitz WI

Labels: MiParea: Respiration 

Organism: Mouse  Tissue;cell: Heart, Skeletal muscle, Fat  Preparation: Isolated mitochondria  Enzyme: Uncoupling protein  Regulation: ADP, mt-Membrane potential  Coupling state: OXPHOS  Pathway: N, S  HRR: Oxygraph-2k, TPP 

2019-08