A Dynamic Substrate Pool Revealed by cryo-EM of a Lipid-Preserved Respiratory Supercomplex

Jeon, Tae Jin; Lee, Seonggyu; Yoo, Suk Hyun; Kim, Myeongbin; Song, Dabin; Ryu, Joong Hyun; Park, Hwangseo; Kim, Deok Soo; Hyun, Jaekyung; Kim, Ho Min; Ryu, Seong Eon

doi:10.1089/ars.2021.0114

Cited by 8 publications

(18 citation statements)

References 61 publications

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“…Nevertheless, our extensive MD simulation sampling (Table 1 and Methods) and comparison of dynamics, hydration, and energetics of Q with the structurally characterized site 4 provide support to our proposal. Furthermore, the recent structural results reveal the binding of Q molecules outside the Q tunnel and in buried regions of complex I [29,30], which is in good agreement with our current proposal and with earlier chemical biology experiments and MD simulations [21,26,28].…”

Section: Mechanistic Implicationssupporting

confidence: 91%

“…Beyond the canonical model in which the structurally characterized Q tunnel is the only path responsible for binding and reduction of Q, chemical biology experiments and molecular dynamics (MD) simulations have suggested additional routes through which Q (or its analogs) can transit towards the reaction site near N2 [21,26–28]. This viewpoint has gained support from recent structural data in which Q molecules have been observed to bind outside the canonical Q tunnel [29,30] (see Fig. S1).…”

Section: Figmentioning

confidence: 99%

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Docking and molecular simulations reveal a quinone‐binding site on the surface of respiratory complex I

et al. 2022

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The first component of the mitochondrial electron transport chain is respiratory complex I. Several high‐resolution structures of complex I from different species have been resolved. However, despite these significant achievements, the mechanism of redox‐coupled proton pumping remains elusive. Here, we combined atomistic docking, molecular dynamics simulations, and site‐directed mutagenesis on respiratory complex I from Yarrowia lipolytica to identify a quinone (Q)‐binding site on its surface near the horizontal amphipathic helices of ND1 and NDUFS7 subunits. The surface‐bound Q makes stable interactions with conserved charged and polar residues, including the highly conserved Arg72 from the NDUFS7 subunit. The binding and dynamics of a Q molecule at the surface‐binding site raise interesting possibilities about the mechanism of complex I, which are discussed.

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Section: Mechanistic Implicationssupporting

confidence: 91%

Section: Figmentioning

confidence: 99%

Docking and molecular simulations reveal a quinone‐binding site on the surface of respiratory complex I

et al. 2022

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“…CI and CIII both showed the flux control coefficient of 1, which led to the conclusion that ubiquinone was exclusively used by the respirasome that held it. Consistent with the flux control analysis, out recent structural studies on bovine mitochondrial respirasome revealed a dynamic substrate pool between CI and CIII (Figure 3) (Jeon et al, 2022). The substrate pool, which may vary its size depending on metabolic needs, can contribute to substrate channeling for efficient electron transfer.…”

Section: Substrate Pool and Channelingsupporting

confidence: 73%

“…Though the existence of supercomplexes is irrefutable at this point, our recent research has shown that prolonged exposure to digitonin can have detrimental effects on supercomplexes by excessively extracting lipids (Jeon et al, 2022). The existence of the supercomplex may be a natural phenomenon, but how natural the properties, structure, and activity of the purified supercomplexes is an enigma to be solved in the future.…”

Section: Supercomplex Assembly Modelsmentioning

confidence: 99%

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Assembly and functional role of mitochondrial respiratory supercomplex

Yoo

Ryu

2023

BIO DESIGN

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The electron transport chain is the final stage of aerobic respiration. NADH or succinate from glycolysis, fatty acid oxidation, or tricarboxylic acid cycle passes its electrons to the electron transport chain on the inner mitochondrial membrane. As the electrons are passed on along the electron transport chain, the electrons' energy potential is used to pump protons into the space between the inner and outer mitochondrial membranes. The electrochemical gradient resulting from these pumped protons is used to fuel ATP synthesis. Regulation of the electron transport chain plays a role in energy metabolism-related diseases such as obesity, insulin resistance, hepatic steatosis, and diabetes mellitus. Dysfunction of electron transport chain regulation contributes to neurodegenerative diseases such as Alzheimer's or Parkinson's disease, too. The mitochondrial electron transport chain is the source of leaked electrons creating reactive oxygen species and contributing to aging. In this review, we will discuss current knowledge about the respiratory supercomplexes of the electron transport chain and the issues in disputes.

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Mitochondrial respiratory complex I can be inhibited via bypassing the ubiquinone‐accessing tunnel

Otani,

Masuya,

Miyoshi

et al. 2024

FEBS Letters

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Mitochondrial NADH–ubiquinone oxidoreductase (complex I) couples electron transfer from NADH to ubiquinone with proton translocation in its membrane part. Structural studies have identified a long (~ 30 Å), narrow, tunnel‐like cavity within the enzyme, through which ubiquinone may access a deep reaction site. Although various inhibitors are considered to block the ubiquinone reduction by occupying the tunnel's interior, this view is still debatable. We synthesized a phosphatidylcholine‐quinazoline hybrid compound (PC‐Qz1), in which a quinazoline‐type toxophore was attached to the sn‐2 acyl chain to prevent it from entering the tunnel. However, PC‐Qz1 inhibited complex I and suppressed photoaffinity labeling by another quinazoline derivative, [125I]AzQ. This study provides further experimental evidence that is difficult to reconcile with the canonical ubiquinone‐accessing tunnel model.

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A Dynamic Substrate Pool Revealed by cryo-EM of a Lipid-Preserved Respiratory Supercomplex

Cited by 8 publications

References 61 publications

Docking and molecular simulations reveal a quinone‐binding site on the surface of respiratory complex I

Docking and molecular simulations reveal a quinone‐binding site on the surface of respiratory complex I

Assembly and functional role of mitochondrial respiratory supercomplex

Mitochondrial respiratory complex I can be inhibited via bypassing the ubiquinone‐accessing tunnel

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