Superoxide generation by complex III: From mechanistic rationales to functional consequences

Bleier, Lea; Dröse, Stefan

doi:10.1016/j.bbabio.2012.12.002

Cited by 294 publications

(246 citation statements)

References 180 publications

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“…With the proposed mechanism, it can be appreciated that energetic states associated with oxidation of QH 2 by cyt b 6 f/cyt bc 1 are positioned at levels that allow smooth catalysis while limiting released ROS to perhaps just signaling levels that carefully report the dynamically changing redox state of cofactors (6,34). It is proposed that the SQ-FeS metastable state serves as a "buffer" for electrons that are unable to be relegated from Q p through the low-potential chain.…”

Section: Discussionmentioning

confidence: 99%

Metastable radical state, nonreactive with oxygen, is inherent to catalysis by respiratory and photosynthetic cytochromes bc ₁ / b ₆ f

Sarewicz

Bujnowicz

Bhaduri

et al. 2017

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

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Oxygenic respiration and photosynthesis based on quinone redox reactions face a danger of wasteful energy dissipation by diversion of the productive electron transfer pathway through the generation of reactive oxygen species (ROS). Nevertheless, the widespread quinone oxido-reductases from the cytochrome bc family limit the amounts of released ROS to a low, perhaps just signaling, level through an as-yet-unknown mechanism. Here, we propose that a metastable radical state, nonreactive with oxygen, safely holds electrons at a local energetic minimum during the oxidation of plastohydroquinone catalyzed by the chloroplast cytochrome b 6 f. This intermediate state is formed by interaction of a radical with a metal cofactor of a catalytic site. Modulation of its energy level on the energy landscape in photosynthetic vs. respiratory enzymes provides a possible mechanism to adjust electron transfer rates for efficient catalysis under different oxygen tensions.cytochrome b 6 f | reactive oxygen species | semiquinone | electron paramagnetic resonance | electron transport P hotosynthetic and respiratory cytochromes bc 1 /b 6 f (Fig. 1A) generate a proton-motive force (pmf) that powers cellular metabolism by using the Gibbs free energy difference (ΔG) between hydroquinone (QH 2 ) derivatives (Fig. 1B) and oxidized soluble electron transfer proteins (e.g., cytochrome c or plastocyanin) (1, 2). To increase the efficiency of this process, which is critical for the yield of the generated pmf, one part of the enzyme recirculates electrons to the quinone pool in the membrane (Q pool), whereas the second part steers the electrons to the cytochrome c pool, powering the electron recirculation (Fig. 1C). This mechanism, which is best established for the cytochrome bc 1 (cyt bc 1 ) (3, 4), with supporting data for the cytochrome b 6 f (cyt b 6 f) (5), discussed in ref. 2, is based on bifurcation of the route for two electrons released upon oxidation of QH 2 at one of the catalytic sites-the Q p site, (Q p ), (Fig. 1D) (3-5). A model for the energetics of this reaction assumes that one electron derived from the two-electron QH 2 donor is transferred, through the high-potential cofactor chain ("steering part" in Fig. 1C) to plastocyanin or cytochrome c, whereas the second electron is transferred across the membrane through low-potential cofactors ("recirculation" part in Fig. 1C).The electronic bifurcation process requires formation of a short-lived and reducing redox intermediate-ubisemiquinone (USQ) or plastosemiquinone (PSQ) (4, 6, 7). However, such an intermediate in an oxygenic environment would readily reduce oxygen to form superoxide radical, (O 2 − ), compromising the efficiency of energy conservation (8). Even in cyt b 6 f where the level of superoxide production through this pathway is at least an order of magnitude greater than that from yeast cyt bc 1 , the branching ratio for electron transfer to O 2 forming O 2 − is only 1-2% of the total flux (6). The low absolute level of O 2 − production in native proteins implies the e...

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Section: Discussionmentioning

confidence: 99%

Metastable radical state, nonreactive with oxygen, is inherent to catalysis by respiratory and photosynthetic cytochromes bc ₁ / b ₆ f

Sarewicz

Bujnowicz

Bhaduri

et al. 2017

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

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“…While the redox hypothesis is driven by the fact that the decrease in ROS levels can be easily explained by decreased substrate (oxygen) availability, the increase of ROS during hypoxia seems counter-intuitive. Generally, some factors favour ROS release from mitochondria: increased lifetime of ubisemiquinone [105], electron backflow through complex II [106], mitochondrial calcium influx [107], activation of mitochondrial potassium channels [108] or mitochondrial hyperpolarisation [109]. While some of the above factors seem unlikely to contribute to HPV, some have indeed been observed in hypoxia.…”

Section: Potential Mechanisms Of Increased Hypoxic Mitochondrial Ros mentioning

confidence: 99%

Oxygen sensing and signal transduction in hypoxic pulmonary vasoconstriction

et al. 2015

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Number 11 in the series "Physiology in respiratory medicine" Edited by R. Naeije, D. Chemla, A. Vonk-Noordegraaf and A.T. Dinh-Xuan Affiliation: Excellence Cluster Cardiopulmonary System, University of Giessen Lung Center, German Center for Lung Research (DZL), Justus-Liebig-University, Giessen, Germany.Correspondence: Norbert Weissmann, Excellence Cluster Cardiopulmonary System, University of Giessen Lung Center, German Center for Lung Research (DZL), Justus-Liebig-University, 35392 Giessen, Germany. E-mail: Norbert.Weissmann@innere.med.uni-giessen.de ABSTRACT Hypoxic pulmonary vasoconstriction (HPV), also known as the von Euler-Liljestrand mechanism, is an essential response of the pulmonary vasculature to acute and sustained alveolar hypoxia. During local alveolar hypoxia, HPV matches perfusion to ventilation to maintain optimal arterial oxygenation. In contrast, during global alveolar hypoxia, HPV leads to pulmonary hypertension. The oxygen sensing and signal transduction machinery is located in the pulmonary arterial smooth muscle cells (PASMCs) of the pre-capillary vessels, albeit the physiological response may be modulated in vivo by the endothelium. While factors such as nitric oxide modulate HPV, reactive oxygen species (ROS) have been suggested to act as essential mediators in HPV. ROS may originate from mitochondria and/or NADPH oxidases but the exact oxygen sensing mechanisms, as well as the question of whether increased or decreased ROS cause HPV, are under debate. ROS may induce intracellular calcium increase and subsequent contraction of PASMCs via direct or indirect interactions with protein kinases, phospholipases, sarcoplasmic calcium channels, transient receptor potential channels, voltage-dependent potassium channels and L-type calcium channels, whose relevance may vary under different experimental conditions. Successful identification of factors regulating HPV may allow development of novel therapeutic approaches for conditions of disturbed HPV. @ERSpublications ROS originating from mitochondria and/or NADPH oxidases may initiate HPV but exact signalling mechanisms are unclear http://ow.ly/SkaGC

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“…The other potential role of this enzyme is related to the observation that under some conditions cytochrome bc 1 can generate reactive oxygen species (ROS) in the form of superoxide (26,83). In fact, cytochrome bc 1 is considered a second, after complex I, source of ROS delivered from components of mitochondrial respiratory chain (33,47).…”

Section: Figurementioning

confidence: 99%

“…From all components of mitochondrial electron transport chain that are considered as possible contributors to mitochondrial ROS (complex I, cytochrome bc 1 , and recently also complex II), only cytochrome bc 1 is an enzyme that appears to release most of superoxide to the intermembrane space (34,123,239), as expected considering the localization of the Q o site (FIGURE 8). This topology of ROS release from the Q o site is proposed to have implications for redox signaling (26,84). Generated superoxide after rapid dismutation to hydrogen peroxide may target components of the antioxidative system both in the intermembrane space and in cytosol (98).…”

Section: Generation Of Reactive Oxygen Speciesmentioning

confidence: 99%

Electronic Connection Between the Quinone and CytochromecRedox Pools and Its Role in Regulation of Mitochondrial Electron Transport and Redox Signaling

Sarewicz

Osyczka

2015

Physiological Reviews

138

141

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Physiol Rev 95: 219 -243, 2015; doi:10.1152/physrev.00006.2014.-Mitochondrial respiration, an important bioenergetic process, relies on operation of four membranous enzymatic complexes linked functionally by mobile, freely diffusible elements: quinone molecules in the membrane and water-soluble cytochromes c in the intermembrane space. One of the mitochondrial complexes, complex III (cytochrome bc 1 or ubiquinol: cytochrome c oxidoreductase), provides an electronic connection between these two diffusible redox pools linking in a fully reversible manner two-electron quinone oxidation/reduction with one-electron cytochrome c reduction/oxidation. Several features of this homodimeric enzyme implicate that in addition to its well-defined function of contributing to generation of proton-motive force, cytochrome bc 1 may be a physiologically important point of regulation of electron flow acting as a sensor of the redox state of mitochondria that actively responds to changes in bioenergetic conditions. These features include the following: the opposing redox reactions at quinone catalytic sites located on the opposite sides of the membrane, the inter-monomer electronic connection that functionally links four quinone binding sites of a dimer into an H-shaped electron transfer system, as well as the potential to generate superoxide and release it to the intermembrane space where it can be engaged in redox signaling pathways. Here we highlight recent advances in understanding how cytochrome bc 1 may accomplish this regulatory physiological function, what is known and remains unknown about catalytic and side reactions within the quinone binding sites and electron transfers through the cofactor chains connecting those sites with the substrate redox pools. We also discuss the developed molecular mechanisms in the context of physiology of mitochondria.

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Superoxide generation by complex III: From mechanistic rationales to functional consequences

Cited by 294 publications

References 180 publications

Metastable radical state, nonreactive with oxygen, is inherent to catalysis by respiratory and photosynthetic cytochromes bc ₁ / b ₆ f

Metastable radical state, nonreactive with oxygen, is inherent to catalysis by respiratory and photosynthetic cytochromes bc ₁ / b ₆ f

Oxygen sensing and signal transduction in hypoxic pulmonary vasoconstriction

Electronic Connection Between the Quinone and CytochromecRedox Pools and Its Role in Regulation of Mitochondrial Electron Transport and Redox Signaling

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Superoxide generation by complex III: From mechanistic rationales to functional consequences

Cited by 294 publications

References 180 publications

Metastable radical state, nonreactive with oxygen, is inherent to catalysis by respiratory and photosynthetic cytochromes bc 1 / b 6 f

Metastable radical state, nonreactive with oxygen, is inherent to catalysis by respiratory and photosynthetic cytochromes bc 1 / b 6 f

Oxygen sensing and signal transduction in hypoxic pulmonary vasoconstriction

Electronic Connection Between the Quinone and CytochromecRedox Pools and Its Role in Regulation of Mitochondrial Electron Transport and Redox Signaling

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Product

Resources

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Metastable radical state, nonreactive with oxygen, is inherent to catalysis by respiratory and photosynthetic cytochromes bc ₁ / b ₆ f

Metastable radical state, nonreactive with oxygen, is inherent to catalysis by respiratory and photosynthetic cytochromes bc ₁ / b ₆ f