Progress in understanding structure–function relationships in respiratory chain complex II

Ackrell, Brian A.C.

doi:10.1016/s0014-5793(99)01749-4

Cited by 126 publications

(92 citation statements)

References 49 publications

(70 reference statements)

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“…The anchor domain was proposed to contain a core of four antiparallel helices comprising helices I, II, IV, and V (4, 26). This model is now supported by two crystal structures (10,27,28).Several lines of experimentation have shown that the membrane domain contains the binding sites for quinone substrates. First, functional anchor polypeptides are required for interaction with quinone substrates (1, 3).…”

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confidence: 74%

The Quinone-binding Sites of the Saccharomyces cerevisiae Succinate-ubiquinone Oxidoreductase

Oyedotun

Lemire

2001

Journal of Biological Chemistry

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The Saccharomyces cerevisiae succinate dehydrogenase (SDH) of the mitochondrial electron transport chain oxidizes succinate and reduces ubiquinone. Using a random mutagenesis approach, we identified functionally important amino acid residues in one of the anchor subunits, Sdh4p. We analyzed three point mutations (F69V, S71A, and H99L) and one nonsense mutation (Y89OCH) that truncates the Sdh4p subunit at the third predicted transmembrane segment. The F69V and the S71A mutations result in greatly impaired respiratory growth in vivo and quinone reductase activities in vitro, with negligible effects on enzyme stability. In contrast, the Y89OCH and the H99L mutations elicit large structural perturbations that impair assembly as evidenced by reduced covalent FAD levels, membrane-associated succinate-phenazine methosulfate reductase activities, and thermal stability. We propose that the Phe-69 and the Ser-71 residues are involved in the formation of a quinone-binding site, whereas the His-99 residue is at the interface of the peripheral and the membrane domains. In addition, the properties of the Y89OCH mutation are consistent with the interpretation that the third transmembrane segment is not involved in catalysis but rather plays an important structural role. The mutant enzymes are differentially sensitive to a quinone analog inhibitor, providing further evidence for a two-quinone binding model in the yeast SDH. Succinate dehydrogenase (SDH),1 also known as complex II or succinate-ubiquinone oxidoreductase, participates in the mitochondrial electron transport by oxidizing succinate to fumarate and transferring the electrons to ubiquinone (1-5). The mitochondrial respiratory chain carries out a series of vectorial reactions that generate an electrochemical potential across the inner mitochondrial membrane, which is then used to drive the synthesis of ATP (6 -9). Membrane-bound fumarate reductases are structurally and functionally related enzymes and are present in anaerobic organisms respiring with fumarate as the terminal electron acceptor (1-4, 10). FRD catalyzes the reduction of fumarate to succinate coupled to the oxidation of quinol, the reverse of the reaction catalyzed by SDH. Both enzymes can catalyze their respective reverse reactions in vitro, and in some cases, in vivo. However, SDH and FRD are physiologically distinct enzymes (2, 4, 11).Generally, SDH is made up of two distinct domains: a dimeric peripheral domain and a monomeric or a dimeric membrane-intrinsic domain. In the yeast Saccharomyces cerevisiae, the peripheral domain, which contains the active site for succinate oxidation, comprises the 67-kDa Sdh1p subunit to which is covalently attached an FAD cofactor (12-16) and the 28-kDa Sdh2p subunit, which contains three iron-sulfur clusters (17, 18). The membrane-intrinsic domain is composed of two hydrophobic subunits, Sdh3p and Sdh4p, of 16.7 and 16.6 kDa, respectively (19 -21). The anchor domain contains a b-type heme and the active site for ubiquinone reduction (22-25). The anchor domain was propo...

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confidence: 74%

The Quinone-binding Sites of the Saccharomyces cerevisiae Succinate-ubiquinone Oxidoreductase

Oyedotun

Lemire

2001

Journal of Biological Chemistry

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“…12 We report here the cellular events deriving from Complex II mutation associated with Leigh's syndrome. This study was conducted also in cellular models in which we mimicked Complex II deficiency by using Complex II inhibitors.…”

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Calcium signalling-dependent mitochondrial dysfunction and bioenergetics regulation in respiratory chain Complex II deficiency

et al. 2010

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Despite advanced knowledge on the genetic basis of oxidative phosphorylation-related diseases, the molecular and/or cellular determinants for tissue-specific dysfunction are not completely understood. Here, we report the cellular events associated with mitochondrial respiratory Complex II deficiency occurring before cell death. Mutation or chronic inhibition of Complex II determined a large increase of basal and agonist-evoked Ca 2 þ signals in the cytosol and the mitochondria, in parallel with mitochondrial dysfunction characterized by membrane potential (Dw mit ) loss, [ATP] reduction and increased reactive oxygen species production. Cytosolic and mitochondrial Ca 2 þ overload are linked to increased endoplasmic reticulum (ER) Ca 2 þ leakage, and to SERCA2b and PMCA proteasome-dependent degradation. Increased [Ca 2 þ ] mit is also contributed by decreased mitochondrial motility and increased ER-mitochondria contact sites. Interestingly, increased intracellular [Ca 2 þ ] activated on the one hand a compensatory Ca 2 þ -dependent glycolytic ATP production and determined on the second hand mitochondrial pathology. These results revealed the primary function for Ca 2 þ signalling in the control of mitochondrial dysfunction and cellular bioenergetics outcomes linked to respiratory chain Complex II deficiency. Mitochondria are the driving force behind life, as mitochondrial oxidative phosphorylation provides the main source of ATP in the cell. In addition to energy production, mitochondria have a crucial function in mediating amino-acid biosynthesis, fatty acid oxidation, intermediate metabolic pathways, free radicals production and Ca 2 þ homeostasis. 1 Mitochondria affect intracellular Ca 2 þ metabolism in two ways: (i) directly by regulating both the amplitude, duration, location and propagation of cytosolic Ca 2 þ elevations and the recycling of Ca 2 þ towards the endoplasmic reticulum (ER) and 2 (ii) indirectly by producing ATP, which is used by Ca 2 þ -dependent ATPases to pump Ca 2 þ out of the cell (by the plasma-membrane Ca 2 þ ATPase: PMCA) or into intracellular stores (by the sarco-ER Ca 2 þ ATPase: SERCA). Conversely, Ca 2 þ entering to the mitochondrial matrix regulates mitochondrial metabolism through the activation of the Ca 2 þ -dependent enzymes of the Krebs cycle. 3 Leigh's syndrome is a rare but severe and fatal encephalopathy of early childhood that is most frequently associated with deficiencies in nucleus-encoded subunits of Complex I (NDUFS3 and NDUFS7), 4,5 Complex II (SDHA), 6 Complex IV (SURF1) 7 or pyruvate dehydrogenase. 8 Despite the identification of the genetic origin of Leigh's syndrome, the molecular and cellular events associated with pathology are not completely understood.Deregulations of intracellular Ca 2 þ signalling have been reported in different models of mitochondrial respiratory chain diseases, 9-11 whereas data on Complex II deficiency are still lacking.Complex II (succinate: ubiquinone (UQ) oxidoreductase) has a central function in oxidative metabolism, being an importan...

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“…These autosomerecessive conditions manifest as childhood encephalopathy, myopathy, adult optic atrophy, and Leigh syndrome. However, mutations in subunit SdhB, SdhC, or SdhD are linked to tumorigenesis in the form of autosome-dominant familial paragangliomas and pheochromocytomas (1,3,16,19,33). Paragangliomas are benign, highly vascular tumors located within sympathetic paraganglia in the head and neck, and they are derived from neural crest cells (38).…”

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confidence: 99%

“…Complex II oxidizes succinate to fumarate and transfers the electrons to ubiquinone through a sequence of steps involving a flavin moiety in SdhA, a set of iron-sulfur clusters in SdhB, a heme group in SdhC, and the ubiquinone binding site in SdhC and SdhD ( Fig. 1) (1,9). When complex II is disrupted at SdhB, SdhC, or SdhD, the succinate dehydrogenase activity within SdhA can remain intact even though overall complex II function is disabled (51).…”

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confidence: 99%

Loss of the SdhB, but Not the SdhA, Subunit of Complex II Triggers Reactive Oxygen Species-Dependent Hypoxia-Inducible Factor Activation and Tumorigenesis

Guzy¹,

Sharma²,

Bell

et al. 2008

Molecular and Cellular Biology

389

340

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Mitochondrial complex II is a tumor suppressor comprised of four subunits (SdhA, SdhB, SdhC, and SdhD). Mutations in any of these should disrupt complex II enzymatic activity, yet defects in SdhA produce bioenergetic deficiency while defects in SdhB, SdhC, or SdhD induce tumor formation. The mechanisms underlying these differences are not known. We show that the inhibition of distal subunits of complex II, either pharmacologically or via RNA interference of SdhB, increases normoxic reactive oxygen species (ROS) production, increases hypoxia-inducible factor alpha (HIF-α) stabilization in an ROS-dependent manner, and increases growth rates in vitro and in vivo without affecting hypoxia-mediated activation of HIF-α. Proximal pharmacologic inhibition or RNA interference of complex II at SdhA, however, does not increase normoxic ROS production or HIF-α stabilization and results in decreased growth rates in vitro and in vivo. Furthermore, the enhanced growth rates resulting from SdhB suppression are inhibited by the suppression of HIF-1α and/or HIF-2α, indicating that the mechanism of SdhB-induced tumor formation relies upon ROS production and subsequent HIF-α activation. Therefore, differences in ROS production, HIF proliferation, and cell proliferation contribute to the differences in tumor phenotype in cells lacking SdhB as opposed to those lacking SdhA.

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Progress in understanding structure–function relationships in respiratory chain complex II

Cited by 126 publications

References 49 publications

The Quinone-binding Sites of the Saccharomyces cerevisiae Succinate-ubiquinone Oxidoreductase

The Quinone-binding Sites of the Saccharomyces cerevisiae Succinate-ubiquinone Oxidoreductase

Calcium signalling-dependent mitochondrial dysfunction and bioenergetics regulation in respiratory chain Complex II deficiency

Loss of the SdhB, but Not the SdhA, Subunit of Complex II Triggers Reactive Oxygen Species-Dependent Hypoxia-Inducible Factor Activation and Tumorigenesis

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