Modulation of complex II-energized respiration in muscle, heart, and brown adipose mitochondria by oxaloacetate and complex I electron flow

Brian D Fink; Liping Yu; William I Sivitz

doi:10.1096/fj.201900690R

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Modulation of complex II-energized respiration in muscle, heart, and brown adipose mitochondria by oxaloacetate and complex I electron flow

Journal article

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Modulation of complex II-energized respiration in muscle, heart, and brown adipose mitochondria by oxaloacetate and complex I electron flow

Brian D Fink, Liping Yu and William I Sivitz

The FASEB journal, Vol.33(11), pp.11696-11705

11/2019

DOI: 10.1096/fj.201900690R

PMCID: PMC6902704

PMID: 31361970

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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 O 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, 1-(3-acetamidophenyl)- 2-(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.-Fink, B. D., Yu, L., Sivitz, W. I. Modulation of complex II-energized respiration in muscle, heart, and brown adipose mitochondria by oxaloacetate and complex I electron flow.

Adenosine Diphosphate - metabolism

Adipose Tissue, Brown - drug effects

Adipose Tissue, Brown - metabolism

Adiposity - drug effects

Adiposity - physiology

Animals

Electron Transport Complex I - metabolism

Male

Mice, Inbred C57BL

Mitochondria - drug effects

Mitochondria - metabolism

Mitochondria, Muscle - drug effects

Mitochondria, Muscle - metabolism

Myocardium - metabolism

Obesity - metabolism

Oxygen Consumption - drug effects

Respiration - drug effects

Succinate Dehydrogenase - metabolism

Succinate Dehydrogenase - pharmacology

Uncoupling Protein 1 - drug effects

Uncoupling Protein 1 - metabolism

Details

Title: Subtitle: Modulation of complex II-energized respiration in muscle, heart, and brown adipose mitochondria by oxaloacetate and complex I electron flow
Creators: Brian D Fink - University of Iowa
Liping Yu - University of Iowa
William I Sivitz - University of Iowa
Resource Type: Journal article
Publication Details: The FASEB journal, Vol.33(11), pp.11696-11705
DOI: 10.1096/fj.201900690R
PMID: 31361970
PMCID: PMC6902704
NLM abbreviation: FASEB J
ISSN: 0892-6638
eISSN: 1530-6860
Grant note: I01 BX000285 / BLRD VA
Language: English
Date published: 11/2019
Academic Unit: Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Medicine Administration; Endocrinology and Metabolism; Internal Medicine
Record Identifier: 9984627209502771

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