Kinetic evidence against partitioning of the ubiquinone pool and the catalytic relevance of respiratory-chain supercomplexes

In mitochondria, four respiratory-chain complexes drive oxidative phosphorylation by sustaining a proton-motive force across the inner membrane that is used to synthesize ATP. The question of how the densely packed proteins of the inner membrane are organized to optimize structure and function has r...

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Veröffentlicht in:Proceedings of the National Academy of Sciences - PNAS 2014-11, Vol.111 (44), p.15735-15740
Hauptverfasser: Blaza, James N., Serreli, Riccardo, Jones, Andrew J. Y., Mohammed, Khairunnisa, Hirst, Judy
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container_issue 44
container_start_page 15735
container_title Proceedings of the National Academy of Sciences - PNAS
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creator Blaza, James N.
Serreli, Riccardo
Jones, Andrew J. Y.
Mohammed, Khairunnisa
Hirst, Judy
description In mitochondria, four respiratory-chain complexes drive oxidative phosphorylation by sustaining a proton-motive force across the inner membrane that is used to synthesize ATP. The question of how the densely packed proteins of the inner membrane are organized to optimize structure and function has returned to prominence with the characterization of respiratory-chain supercomplexes. Supercomplexes are increasingly accepted structural entities, but their functional and catalytic advantages are disputed. Notably, substrate “channeling” between the enzymes in supercomplexes has been proposed to confer a kinetic advantage, relative to the rate provided by a freely accessible, common substrate pool. Here, we focus on the mitochondrial ubiquinone/ubiquinol pool. We formulate and test three conceptually simple predictions of the behavior of the mammalian respiratory chain that depend on whether channeling in supercomplexes is kinetically important, and on whether the ubiquinone pool is partitioned between pathways. Our spectroscopic and kinetic experiments demonstrate how the metabolic pathways for NADH and succinate oxidation communicate and catalyze via a single, universally accessible ubiquinone/ubiquinol pool that is not partitioned or channeled. We reevaluate the major piece of contrary evidence from flux control analysis and find that the conclusion of substrate channeling arises from the particular behavior of a single inhibitor; we explain why different inhibitors behave differently and show that a robust flux control analysis provides no evidence for channeling. Finally, we discuss how the formation of respiratory-chain supercomplexes may confer alternative advantages on energy-converting membranes. Significance Mitochondria produce ATP by using respiration to drive ATP synthase. Respiration is catalyzed by several membrane-bound complexes that are structurally organized into supercomplex assemblies. Supercomplexes have been proposed to confer a catalytic advantage by channeling of substrates between enzymes in the assemblies. Here, we test three simple predictions of the behavior of the mammalian respiratory chain that depend on whether channeling in supercomplexes is kinetically important and show that it is not. We reinterpret previous data taken to support substrate channeling and reveal an alternative explanation for these data. Finally, we discuss alternative proposals for why the respiratory-chain complexes have evolved to form supercomplex structu
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subjects Animals
Biological Sciences
Catalysis
Cattle
Electron Transport - physiology
Electron Transport Complex I - chemistry
Electron Transport Complex I - metabolism
Enzyme substrates
Enzymes
Kinetics
Mitochondria
Mitochondria, Heart - enzymology
Models, Chemical
NAD - chemistry
NAD - metabolism
Organic chemicals
Oxidation
Oxidation-Reduction
P branes
Phosphorylation
Spectral methods
Spectroscopy
Succinic Acid - chemistry
Succinic Acid - metabolism
Ubiquinone - chemistry
Ubiquinone - metabolism
Ungulates
title Kinetic evidence against partitioning of the ubiquinone pool and the catalytic relevance of respiratory-chain supercomplexes
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