Architecture of Succinate Dehydrogenase and Reactive Oxygen Species Generation

Yankovskaya, Victoria; Horsefield, Rob; Törnroth, Susanna; Luna-Chavez, C.; Miyoshi, Hideto; Léger, Christophe; Byrne, Bernadette; Cecchini, Gary; Iwata, So

doi:10.1126/science.1079605

Cited by 803 publications

(734 citation statements)

References 30 publications

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“…In our experiments with RLM, the substrate was succinate, which sends electrons to the respiratory chain through Complex II (succinate dehydrogenase) and ubiquinone. This complex contains heme b, which is not involved in electron transport but which serves as an electron sink to prevent leakage out of the respiratory chain (Yankovskaya et al 2003).…”

Section: Discussionmentioning

confidence: 99%

Interactions of melatonin with mammalian mitochondria. Reducer of energy capacity and amplifier of permeability transition

et al. 2011

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Melatonin, a metabolic product of the amino acid tryptophan, induces a dose-dependent energy drop correlated with a decrease in the oxidative phosphorylation process in isolated rat liver mitochondria. This effect involves a gradual decrease in the respiratory control index and significant alterations in the state 4/state 3 transition of membrane potential (DW). Melatonin, alone, does not affect the insulating properties of the inner membrane but, in the presence of supraphysiological Ca 2? , induces a DW drop and colloid-osmotic mitochondrial swelling. These events are sensitive to cyclosporin A and the inhibitors of Ca 2? transport, indicative of the induction or amplification of the mitochondrial permeability transition. This phenomenon is triggered by oxidative stress induced by melatonin and Ca 2? , with the generation of hydrogen peroxide and the consequent oxidation of sulfydryl groups, glutathione and pyridine nucleotides. In addition, melatonin, again in the presence of Ca 2? , can also induce substantial release of cytochrome C and AIF (apoptosis-inducing factor), thus revealing its potential as a pro-apoptotic agent.

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Section: Discussionmentioning

confidence: 99%

Interactions of melatonin with mammalian mitochondria. Reducer of energy capacity and amplifier of permeability transition

et al. 2011

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“…2B). It is noteworthy that the E. coli enzyme has been reported to crystallize as a trimer and this oligomerization of the protein was suggested to have physiological relevance [49]. Band 7, detected by heme staining (Fig.…”

Section: Detection Of Supercomplexes By Electrophoretic Techniquesmentioning

confidence: 93%

Supramolecular organizations in the aerobic respiratory chain of Escherichia coli

et al. 2011

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a b s t r a c tThe organization of respiratory chain complexes in supercomplexes has been shown in the mitochondria of several eukaryotes and in the cell membranes of some bacteria. These supercomplexes are suggested to be important for oxidative phosphorylation efficiency and to prevent the formation of reactive oxygen species.Here we describe, for the first time, the identification of supramolecular organizations in the aerobic respiratory chain of Escherichia coli, including a trimer of succinate dehydrogenase. Furthermore, two heterooligomerizations have been shown: one resulting from the association of the NADH:quinone oxidoreductases NDH-1 and NDH-2, and another composed by the cytochrome bo 3 quinol:oxygen reductase, cytochrome bd quinol:oxygen reductase and formate dehydrogenase (fdo). These results are supported by blue native-electrophoresis, mass spectrometry and kinetic data of wild type and mutant E . coli strains.

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“…Instead, they recombine with molecular oxygen to enhance superoxide anion radical (O 2 À ) production that leads to induction of apoptosis in the cancer cell. Although it is possible that ROS generation occurs via the FAD site (Yankovskaya et al, 2003;Gottlieb and Tomlinson, 2005), it cannot be excluded that electrons in the case of a dysfunctional CII, interact with oxygen, which is dissolved in the membrane part of CII (Slane et al, 2006). Another possibility is that electrons move to CI by reverse electron transport, where they form O 2 À (Adam-Vizi and Chinopoulos, 2006).…”

Section: Complex II As An Anti-cancer Drug Target L-f Dong Et Almentioning

confidence: 99%

α-Tocopheryl succinate induces apoptosis by targeting ubiquinone-binding sites in mitochondrial respiratory complex II

et al. 2008

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a-Tocopheryl succinate (a-TOS) is a selective inducer of apoptosis in cancer cells, which involves the accumulation of reactive oxygen species (ROS). The molecular target of a-TOS has not been identified. Here, we show that a-TOS inhibits succinate dehydrogenase (SDH) activity of complex II (CII) by interacting with the proximal and distal ubiquinone (UbQ)-binding site (Q P and Q D , respectively). This is based on biochemical analyses and molecular modelling, revealing similar or stronger interaction energy of a-TOS compared to that of UbQ for the Q P and Q D sites, respectively. CybL-mutant cells with dysfunctional CII failed to accumulate ROS and underwent apoptosis in the presence of a-TOS. Similar resistance was observed when CybL was knocked down with siRNA. Reconstitution of functional CII rendered CybL-mutant cells susceptible to a-TOS. We propose that a-TOS displaces UbQ in CII causing electrons generated by SDH to recombine with molecular oxygen to yield ROS. Our data highlight CII, a known tumour suppressor, as a novel target for cancer therapy.

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Architecture of Succinate Dehydrogenase and Reactive Oxygen Species Generation

Cited by 803 publications

References 30 publications

Interactions of melatonin with mammalian mitochondria. Reducer of energy capacity and amplifier of permeability transition

Interactions of melatonin with mammalian mitochondria. Reducer of energy capacity and amplifier of permeability transition

Supramolecular organizations in the aerobic respiratory chain of Escherichia coli

α-Tocopheryl succinate induces apoptosis by targeting ubiquinone-binding sites in mitochondrial respiratory complex II

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