Molecular Oxygen Binding in the Mitochondrial Electron Transfer Flavoprotein

Husen, Peter; Nielsen, Claus; Martino, Carlos F.; Solov’yov, Ilia A.

doi:10.1021/acs.jcim.9b00702

Cited by 17 publications

(31 citation statements)

References 60 publications

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“…To study the binding and dynamics of superoxide after an electron transfer event at the Q o -site, a set of 100 MD simulations starting with

bound in place of O 2 in the pocket depicted on Supplementary Figure S5 in the SM were carried out for each of the two models following an approach previously used to model O 2 binding and unbinding in proteins ( Husen et al, 2019 ). All simulations were continued until

unbinding was observed.…”

Section: Resultsmentioning

confidence: 99%

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Modeling the Energy Landscape of Side Reactions in the Cytochrome bc1 Complex

Husen

Solov’yov

2021

Front. Chem.

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Much of the metabolic molecular machinery responsible for energy transduction processes in living organisms revolves around a series of electron and proton transfer processes. The highly redox active enzymes can, however, also pose a risk of unwanted side reactions leading to reactive oxygen species, which are harmful to cells and are a factor in aging and age-related diseases. Using extensive quantum and classical computational modeling, we here show evidence of a particular superoxide production mechanism through stray reactions between molecular oxygen and a semiquinone reaction intermediate bound in the mitochondrial complex III of the electron transport chain, also known as the cytochrome bc1 complex. Free energy calculations indicate a favorable electron transfer from semiquinone occurring at low rates under normal circumstances. Furthermore, simulations of the product state reveal that superoxide formed at the Qo-site exclusively leaves the bc1 complex at the positive side of the membrane and escapes into the intermembrane space of mitochondria, providing a critical clue in further studies of the harmful effects of mitochondrial superoxide production.

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“…To study the binding and dynamics of superoxide after an electron transfer event at the Q o -site, a set of 100 MD simulations starting with

unbinding was observed.…”

Section: Resultsmentioning

confidence: 99%

“…In both cases, the bound O 2 was changed to

. For each model, 100 replicate MD simulations with

initially bound were then carried out for long enough to observe it unbind, following an approach previously used to model O 2 binding in proteins ( Husen et al, 2019 ).…”

Section: Methodsmentioning

confidence: 99%

Modeling the Energy Landscape of Side Reactions in the Cytochrome bc1 Complex

Husen

Solov’yov

2021

Front. Chem.

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“…The isoalloxazine ring of the flavin cofactor can undergo thermally driven redox chemistry, as shown in Figure 3. The different redox states of flavin play essential roles in various electron transfer processes and consequently are crucial for a variety of important biological functions, including energy production, oxidation, DNA repair, RNA methylation, apoptosis, protein folding, cytoskeleton dynamics, detoxification, neural development, biosynthesis, the circadian clock, photosynthesis, light emission and biodegradation 419,[448][449][450][451][452][453][454][455][456][457][458][459] . Different forms of transient radical 20/72 pair intermediates can be created during reactions catalysed by flavin-dependent enzymes, including [FADH ...O -2 ] 460-462 .…”

Section: Beyond Cryptochrome-based Radical Pairsmentioning

confidence: 99%

Magnetic field effects in biology from the perspective of the radical pair mechanism

Zadeh-Haghighi¹,

Simon²

2022

Preprint

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A large and growing body of research shows that weak magnetic fields can significantly influence various biological systems, including plants, animals, and humans. However, the underlying mechanisms behind these phenomena remain elusive. It is remarkable that the magnetic energies implicated in these effects are much smaller than thermal energies. Here we review these observations, of which there are now hundreds, and we suggest that a viable explanation is provided by the radical pair mechanism, which involves the quantum dynamics of the electron and nuclear spins of naturally occurring transient radical molecules. While the radical pair mechanism has been studied in detail in the context of avian magnetoreception, the studies reviewed here show that magnetosensitivity is widespread throughout biology. We review magnetic field effects on various physiological functions, organizing them based on the type of the applied magnetic fields, namely static, hypomagnetic, and oscillating magnetic fields, as well as isotope effects. We then review the radical pair mechanism as a potential unifying model for the described magnetic field effects, and we discuss plausible candidate molecules that might constitute the radical pairs. We review recent studies proposing that the quantum nature of the radical pairs provides promising explanations for xenon anesthesia, lithium effects on hyperactivity, magnetic field and lithium effects on the circadian clock, and hypomagnetic field effects on neurogenesis and microtubule assembly. We conclude by discussing future lines of investigation in this exciting new area of quantum biology related to weak magnetic field effects.

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“…Superoxide formation may originate due to the transfer of electrons from the ETFQOR to the mitochondrial ubiquinone pool [325]. Either an electron leak from flavin to the oxygen leading to radical pair formation produces superoxide within ETFQOR itself [326]; or since ETFQOR needs ubiquinon (Q), reduced after accepting two electrons from the ETF to ubiquinol (QH 2 ), it effectively competes with the mitochondrial respiratory chain complex I. Since QH 2 binds to the complex I Q-binding site, it allows a feedback inhibition of the ongoing Q reduction to QH 2 within complex I.…”

Section: Mechanism Of Insulin Secretion Stimulated By Branched-chain Ketoacidsmentioning

confidence: 99%

The Pancreatic β-Cell: The Perfect Redox System

et al. 2021

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Pancreatic β-cell insulin secretion, which responds to various secretagogues and hormonal regulations, is reviewed here, emphasizing the fundamental redox signaling by NADPH oxidase 4- (NOX4-) mediated H2O2 production for glucose-stimulated insulin secretion (GSIS). There is a logical summation that integrates both metabolic plus redox homeostasis because the ATP-sensitive K+ channel (KATP) can only be closed when both ATP and H2O2 are elevated. Otherwise ATP would block KATP, while H2O2 would activate any of the redox-sensitive nonspecific calcium channels (NSCCs), such as TRPM2. Notably, a 100%-closed KATP ensemble is insufficient to reach the −50 mV threshold plasma membrane depolarization required for the activation of voltage-dependent Ca2+ channels. Open synergic NSCCs or Cl− channels have to act simultaneously to reach this threshold. The resulting intermittent cytosolic Ca2+-increases lead to the pulsatile exocytosis of insulin granule vesicles (IGVs). The incretin (e.g., GLP-1) amplification of GSIS stems from receptor signaling leading to activating the phosphorylation of TRPM channels and effects on other channels to intensify integral Ca2+-influx (fortified by endoplasmic reticulum Ca2+). ATP plus H2O2 are also required for branched-chain ketoacids (BCKAs); and partly for fatty acids (FAs) to secrete insulin, while BCKA or FA β-oxidation provide redox signaling from mitochondria, which proceeds by H2O2 diffusion or hypothetical SH relay via peroxiredoxin “redox kiss” to target proteins.

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Molecular Oxygen Binding in the Mitochondrial Electron Transfer Flavoprotein

Cited by 17 publications

References 60 publications

Modeling the Energy Landscape of Side Reactions in the Cytochrome bc1 Complex

Modeling the Energy Landscape of Side Reactions in the Cytochrome bc1 Complex

Magnetic field effects in biology from the perspective of the radical pair mechanism

The Pancreatic β-Cell: The Perfect Redox System

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