The architecture of the mammalian respirasome

Gu, Junping; Wu, Meng; Guo, Runyu; Yan, Kaige; Lei, Jianlin; Gao, Ning; Yang, Maojun

doi:10.1038/nature19359

Cited by 313 publications

(299 citation statements)

References 67 publications

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“…For example, the presence of the supercomplex of aerobic respiratory complexes, complexes I, III, and IV, was demonstrated and the structure was characterized by cryoelectron microscopy (23,24). It is likely that the supercomplex formation of the respiratory complexes contributes to effective electron transfer for aerobic respiration.…”

Section: Resultsmentioning

confidence: 99%

Dynamics of nitric oxide controlled by protein complex in bacterial system

Terasaka

Yamada

Wang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Nitric oxide (NO) plays diverse and significant roles in biological processes despite its cytotoxicity, raising the question of how biological systems control the action of NO to minimize its cytotoxicity in cells. As a great example of such a system, we found a possibility that NO-generating nitrite reductase (NiR) forms a complex with NOdecomposing membrane-integrated NO reductase (NOR) to efficiently capture NO immediately after its production by NiR in anaerobic nitrate respiration called denitrification. The 3.2-Å resolution structure of the complex of one NiR functional homodimer and two NOR molecules provides an idea of how these enzymes interact in cells, while the structure may not reflect the one in cells due to the membrane topology. Subsequent all-atom molecular dynamics (MD) simulations of the enzyme complex model in a membrane and structure-guided mutagenesis suggested that a few interenzyme salt bridges and coulombic interactions of NiR with the membrane could stabilize the complex of one NiR homodimer and one NOR molecule and contribute to rapid NO decomposition in cells. The MD trajectories of the NO diffusion in the NiR:NOR complex with the membrane showed that, as a plausible NO transfer mechanism, NO released from NiR rapidly migrates into the membrane, then binds to NOR. These results help us understand the mechanism of the cellular control of the action of cytotoxic NO.is a diffusible radical gas molecule that has been recognized as an integral signaling molecule in eukaryotes and bacteria (1, 2). NO plays pivotal roles in vasodilation, smooth muscle relaxation, neurotransmission, and the immune system in mammals. In bacteria, NO is also involved in several biological processes such as biofilm formation, quorum sensing, and symbiosis. NO is synthesized from L-arginine by an enzyme called nitric oxide synthase (NOS). In mammals, NO activates an NO receptor, soluble guanylate cyclase (sGC), upon the binding to heme in sGC, which induces the formation of signaling molecule, cGMP, from GTP. Currently, an NO binding protein homologous to the heme domain of sGC is thought to participate in bacterial NO signaling pathways (2). However, NO is a highly cytotoxic gas and easily reacts with biomolecules, despite its essential function. Thus, regulation of the cellular action of NO is crucial.Some bacteria would be exposed to large amounts of NO during denitrification, which implies that the control of NO dynamics is indispensable to minimize the cytotoxic effects of NO in such bacteria. Denitrification is a form of microbial anaerobic respiration by bacteria living in oxygen-limited environments in which the sequential reduction of nitrate to dinitrogen (NO 3 − → NO 2 − → NO → N 2 O → N 2 ) is coupled to bioenergy production. Denitrification is also crucial for the survival of some pathogenic bacteria inside host cells (3, 4). For example, Pseudomonas aeruginosa is a major opportunistic pathogen that survives through denitrification in hypoxic and anoxic environments such as the lungs of cystic fibros...

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Section: Resultsmentioning

confidence: 99%

Dynamics of nitric oxide controlled by protein complex in bacterial system

Terasaka

Yamada

Wang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…In contrast, recent structures of the respirasome not only show minimal inter-protein contact between CI and CIII, but also that the quinone/quinol-binding sites are a substantial ∼100 Å distance apart and not oriented to facilitate channeling (Bauler et al., 2010, Gu et al., 2016, Guo et al., 2017, Letts et al., 2016). …”

Section: Discussionmentioning

confidence: 99%

“…In a less restrictive model it has also been proposed that, although exchange with the outside is not precluded, under high turnover conditions quinone/quinol react preferentially within the supercomplex (Lenaz et al., 2016, Letts et al., 2016) due to the enzyme proximities. Alternatively, recent structures of the mammalian respirasome clearly show that the substrate-binding sites in CI and CIII are separated by ∼100 Å, with no mediating protein to facilitate channeling between them (Gu et al., 2016, Guo et al., 2017, Letts et al., 2016, Milenkovic et al., 2017, Wu et al., 2016). Similarly, the structures reveal no barriers to the free diffusion of cytochrome c (Letts et al., 2016, Milenkovic et al., 2017), which has been shown by biophysical methods to diffuse freely along the membrane and not be localized to a single supercomplex (Trouillard et al., 2011).…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial Supercomplexes Do Not Enhance Catalysis by Quinone Channeling

2018

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SummaryMitochondrial respiratory supercomplexes, comprising complexes I, III, and IV, are the minimal functional units of the electron transport chain. Assembling the individual complexes into supercomplexes may stabilize them, provide greater spatiotemporal control of respiration, or, controversially, confer kinetic advantages through the sequestration of local quinone and cytochrome c pools (substrate channeling). Here, we have incorporated an alternative quinol oxidase (AOX) into mammalian heart mitochondrial membranes to introduce a competing pathway for quinol oxidation and test for channeling. AOX substantially increases the rate of NADH oxidation by O2 without affecting the membrane integrity, the supercomplexes, or NADH-linked oxidative phosphorylation. Therefore, the quinol generated in supercomplexes by complex I is reoxidized more rapidly outside the supercomplex by AOX than inside the supercomplex by complex III. Our results demonstrate that quinone and quinol diffuse freely in and out of supercomplexes: substrate channeling does not occur and is not required to support respiration.

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“…These complexes have long been recognized as discrete entities embedded within the inner mitochondrial membrane, but they are also found as respiratory supercomplexes. The crystal structures of two functional supercomplexes (supercomplexes I and III) and the fully functional respirasome (consisting of complexes I, III, and IV) have recently been elucidated (12,32,55).…”

Section: The Dual Genetic Control Of Mitochondrial Functionmentioning

confidence: 99%

Recent Advances in Mitochondrial Disease

Craven

Alston

Taylor

et al. 2017

Annu. Rev. Genom. Hum. Genet.

233

198

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Mitochondrial disease is a challenging area of genetics because two distinct genomes can contribute to disease pathogenesis. It is also challenging clinically because of the myriad of different symptoms and, until recently, a lack of a genetic diagnosis in many patients. The last five years has brought remarkable progress in this area. We provide a brief overview of mitochondrial origin, function, and biology, which are key to understanding the genetic basis of mitochondrial disease. However, the primary purpose of this review is to describe the recent advances related to the diagnosis, genetic basis, and prevention of mitochondrial disease, highlighting the newly described disease genes and the evolving methodologies aimed at preventing mitochondrial DNA disease transmission.

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The architecture of the mammalian respirasome

Cited by 313 publications

References 67 publications

Dynamics of nitric oxide controlled by protein complex in bacterial system

Dynamics of nitric oxide controlled by protein complex in bacterial system

Mitochondrial Supercomplexes Do Not Enhance Catalysis by Quinone Channeling

Recent Advances in Mitochondrial Disease

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