BBA - Bioenergetics (v.1827, #5)

The role of complex II in disease by Attje S. Hoekstra; Jean-Pierre Bayley (543-551).
Genetically defined mitochondrial deficiencies that result in the loss of complex II function lead to a range of clinical conditions. An array of tumor syndromes caused by complex II-associated gene mutations, in both succinate dehydrogenase and associated accessory factor genes (SDHA, SDHB, SDHC, SDHD, SDHAF1, SDHAF2), have been identified over the last 12 years and include hereditary paraganglioma–pheochromocytomas, a diverse group of renal cell carcinomas, and a specific subtype of gastrointestinal stromal tumors (GIST). In addition, congenital complex II deficiencies due to inherited homozygous mutations of the catalytic components of complex II (SDHA and SDHB) and the SDHAF1 assembly factor lead to childhood disease including Leigh syndrome, cardiomyopathy and infantile leukodystrophies. The role of complex II subunit gene mutations in tumorigenesis has been the subject of intensive research and these data have led to a variety of compelling hypotheses. Among the most widely researched are the stabilization of hypoxia inducible factor 1 under normoxia, and the generation of reactive oxygen species due to defective succinate:ubiquinone oxidoreductase function. Further progress in understanding the role of complex II in disease, and in the development of new therapeutic approaches, is now being hampered by the lack of relevant cell and animal models. This article is part of a Special Issue entitled: Respiratory complex II: Role in cellular physiology and disease.► Heterozygous SDH mutations cause an array of tumor syndromes. ► Homozygous SDH mutations generally lead to infantile disease. ► SDH accessory factor gene mutations can cause both types of disease. ► SDH-associated tumors show loss of SDHB protein expression.
Keywords: Paraganglioma; Pheochromocytoma; Renal cell carcinoma; Gastrointestinal stromal tumor; Carney–Stratakis syndrome; Leigh syndrome;

Mitochondrial complex II, a novel target for anti-cancer agents by Katarina Kluckova; Ayanachew Bezawork-Geleta; Jakub Rohlena; Lanfeng Dong; Jiri Neuzil (552-564).
With the arrival of the third millennium, in spite of unprecedented progress in molecular medicine, cancer remains as untamed as ever. The complexity of tumours, dictating the potential response of cancer cells to anti-cancer agents, has been recently highlighted in a landmark paper by Weinberg and Hanahan on hallmarks of cancer [1]. Together with the recently published papers on the complexity of tumours in patients and even within the same tumour (see below), the cure for this pathology seems to be an elusive goal. Indisputably, the strategy ought to be changed, searching for targets that are generally invariant across the landscape of neoplastic diseases. One such target appears to be the mitochondrial complex II (CII) of the electron transfer chain, a recent focus of research. We document and highlight this particularly intriguing target in this review paper and give examples of drugs that use CII as their molecular target. This article is part of a Special Issue entitled: Respiratory complex II: Role in cellular physiology and disease.► Mitochondrial complex II is a novel, intriguing target for anti-cancer drugs. ► Targeting complex II is a selective way to treat cancer. ► The succinate quinone reductase activity of complex II is of particular interest. ► Vitamin E analogues are clinically interesting agents acting on complex II.
Keywords: Mitochondrion; Complex II; Anti-cancer agent; Cancer therapy; Mitocan;

I review here the evidence that complex II of the respiratory chain (RC) constitutes a general sensor for apoptosis induction. This concept emerged from work on neurodegenerative diseases and from recent data on metabolic alterations in cancer cells affecting the RC and in particular on mutations of complex II subunits. It is also supported by experiments with many anticancer compounds that compared the apoptosis sensitivities of complex II-deficient versus WT cells. These results are explained by the mechanistic understanding of how complex II mediates the diverse range of apoptosis signals. This protein aggregate is specifically activated for apoptosis by pH change as a common and early feature of dying cells. This leads to the dissociation of its SDHA and SDHB subunits from the remaining membrane-anchored subunits and the consequent block of it enzymatic SQR activity, while its SDH activity, which is contained in the SDHA/SDHB subcomplex, remains intact. The uncontrolled SDH activity then generates excessive amounts of reactive oxygen species for the demise of the cell. Future studies on these mitochondrial processes will help refine this model, unravel the contribution of mutations in complex II subunits as the cause of degenerative neurological diseases and tumorigenesis, and aid in discovering novel interference options. This article is part of a Special Issue entitled: Respiratory complex II: Role in cellular physiology and disease.► Complex II is a crucial and general sensor for numerous apoptosis signals. ► The pH drop during cell death leads to the specific disintegration of this complex. ► This causes an excessive generation of reactive oxygen species and cell death. ► A better understanding of this process will help unravel the causes of diseases.
Keywords: Complex II; Apoptosis; Reactive oxygen species;

Germ line heterozygous mutations in the structural subunit genes of mitochondrial complex II (succinate dehydrogenase; SDH) and the regulatory gene SDHAF2 predispose to paraganglioma tumors which show constitutive activation of hypoxia inducible pathways. Mutations in SDHD and SDHAF2 cause highly penetrant multifocal tumor development after a paternal transmission, whereas maternal transmission rarely, if ever, leads to tumor development. This transmission pattern is consistent with genomic imprinting. Recent molecular evidence supports a model for tissue-specific imprinted regulation of the SDHD gene by a long range epigenetic mechanism. In addition, there is evidence of SDHB mRNA editing in peripheral blood mononuclear cells and long-term balancing selection operating on the SDHA gene. Regulation of SDH subunit expression by diverse epigenetic mechanisms implicates a crucial dosage-dependent role for SDH in oxygen homeostasis. This article is part of a Special Issue entitled: Respiratory complex II: Role in cellular physiology and disease.► Parent-of-origin effects in inheritance of paraganglioma tumors are discussed. ► A long range epigenetic mechanism may account for genomic imprinting of SDHD. ► Diverse regulatory mechanisms of complex II suggest a crucial role in oxygen homeostasis.
Keywords: Mitochondrial complex II; Succinate dehydrogenase; Paraganglioma; Imprinting; SDHD;

The production of reactive oxygen species by the mitochondrial complex II (succinate:ubiquinone oxidoreductase) recently has gained broad scientific interest. Depending on the (patho)physiological situation, ROS produced or triggered by complex II can have either beneficial or deleterious effects. This ambivalence can be explained mechanistically by the diverse role of complex II on mitochondrial ROS production: it can be a source as well as a suppressor or enhancer of ROS generation by other respiratory chain complexes. Since complex II directly links the respiratory chain to the tricarboxylic acid (TCA) cycle, the TCA-cycle intermediates – especially oxaloacetate that acts as a high affinity endogenous inhibitor – have major impact on complex II-related ROS release. The review relates the diverse effects of complex II activity on the mitochondrial ROS production that have been observed during cardioprotective ischemic or pharmacological preconditioning and the oxidative burst that occurs during ischemia/reperfusion. This article is part of a Special Issue entitled: Respiratory complex II: Role in cellular physiology and disease.► The differential influence of complex II on mitochondrial ROS production is reviewed. ► Complex II can be a source or a modulator of mitochondrial ROS. ► A connection to ischemia/reperfusion and preconditioning is discussed.
Keywords: Complex II; Succinate:ubiquinone oxidoreductase; Mitochondria; Reactive oxygen species; Ischemic preconditioning; Pharmacological preconditioning;

Model animals for the study of oxidative stress from complex II by Takamasa Ishii; Masaki Miyazawa; Hiromi Onouchi; Kayo Yasuda; Phil S. Hartman; Naoaki Ishii (588-597).
Mitochondria play a role of energy production and produce intracellular reactive oxygen species (ROS), especially superoxide anion (O2 •−) as a byproduct of energy metabolism at the same time. O2 •− is converted from oxygen and is overproduced by excessive electron leakage from the mitochondrial respiratory chain. It is well known that mitochondrial complexes I and III in the electron transport system are the major endogenous ROS sources. We have previously demonstrated that mutations in complex II can result in excessive ROS (specifically in SDHC: G71E in Caenorhabditis elegans, I71E in Drosophila and V69E in mouse). Moreover, this results in premature death in C. elegans and Drosophila as well as tumorigenesis in mouse embryonic fibroblast cells. In humans, it has been reported that mutations in SDHB, SDHC or SDHD, which are the subunits of mitochondrial complex II, often result in inherited head and neck paragangliomas (PGLs). Recently, we established Tet-mev-1 conditional transgenic mice using our uniquely developed Tet-On/Off system, which can induce the mutated SDHC gene to be equally and competitively expressed compared to the endogenous wild-type SDHC gene. These mice experienced mitochondrial respiratory chain dysfunction that resulted in oxidative stress. The mitochondrial oxidative stress caused excessive apoptosis in several tissues leading to low-birth-weight infants and growth retardation during neonatal developmental phase in Tet-mev-1 mice. Tet-mev-1 mice also displayed precocious age-dependent corneal physiological changes, delayed corneal epithelialization, decreased corneal endothelial cells, thickened Descemet's membrane and thinning of parenchyma with corneal pathological dysfunctions such as keratitis, Fuchs' corneal dystrophy (FCD) and probably keratoconus after the normal development and growth phase. Here, we review the relationships between mitochondrial oxidative stress and phenomena in mev-1 animal models with mitochondrial complex II SDHC mutations. This article is part of a Special Issue entitled: Respiratory complex II: Role in cellular physiology and disease.Display Omitted► We isolated C. elegans mev-1(kn-1) mutant causes premature death by oxidative stress. ► We constructed mev-1-mimic Drosophila models and Tet-mev-1 mice with SDHC mutation. ► SDHC mutation causes electron leak from complex II resulting in ROS production. ► mev-1-mimic cells cause the tumorigenic transformation with nuclear hypermutability. ► mev-1 animals induce accelerated aging phenomena with excessive apoptosis.
Keywords: SDHC; Aging; Tumorigenesis; Apoptosis; Oxidative stress; Reactive oxygen species;

Physiological consequences of complex II inhibition for aging, disease, and the mKATP channel by Andrew P. Wojtovich; C. Owen Smith; Cole M. Haynes; Keith W. Nehrke; Paul S. Brookes (598-611).
In recent years, it has become apparent that there exist several roles for respiratory complex II beyond metabolism. These include: (i) succinate signaling, (ii) reactive oxygen species (ROS) generation, (iii) ischemic preconditioning, (iv) various disease states and aging, and (v) a role in the function of the mitochondrial ATP-sensitive K+ (mKATP) channel. This review will address the involvement of complex II in each of these areas, with a focus on how complex II regulates or may be involved in the assembly of the mKATP. This article is part of a Special Issue entitled: Respiratory complex II: Role in cellular physiology and disease.► The role of complex II in assembly & regulation of the mKATP channel will be discussed. ► We propose a unifying hypothesis on how mKATP and complex II regulate bioenergetics. ► We also discuss the role of complex II and mKATP in disease pathology & protective signaling.
Keywords: ATP sensitive potassium channel; mKATP; Preconditioning; Ischemia; Succinate dehydrogenase; Diazoxide;

The mitochondrial protein import machinery has multiple connections to the respiratory chain by Bogusz Kulawiak; Jan Höpker; Michael Gebert; Bernard Guiard; Nils Wiedemann; Natalia Gebert (612-626).
The mitochondrial inner membrane harbors the complexes of the respiratory chain and protein translocases required for the import of mitochondrial precursor proteins. These complexes are functionally interdependent, as the import of respiratory chain precursor proteins across and into the inner membrane requires the membrane potential. Vice versa the membrane potential is generated by the proton pumping complexes of the respiratory chain. Besides this basic codependency four different systems for protein import, processing and assembly show further connections to the respiratory chain. The mitochondrial intermembrane space import and assembly machinery oxidizes cysteine residues within the imported precursor proteins and is able to donate the liberated electrons to the respiratory chain. The presequence translocase of the inner membrane physically interacts with the respiratory chain. The mitochondrial processing peptidase is homologous to respiratory chain subunits and the carrier translocase of the inner membrane even shares a subunit with the respiratory chain. In this review we will summarize the import of mitochondrial precursor proteins and highlight these special links between the mitochondrial protein import machinery and the respiratory chain. This article is part of a Special Issue entitled: Respiratory complex II: Role in cellular physiology and disease.► Mitochondrial protein import and the respiratory chain are interdependent. ► Electrons released by oxidative import are donated to the respiratory chain. ► The presequence translocases is physically connected to the respiratory chain. ► The mitochondrial presequence peptidase is homologous to subunits of complex III. ► The carrier translocase contains a subunit of complex II.
Keywords: Inner membrane; Mitochondrion; Protein import; Respiratory chain; Succinate dehydrogenase;

Emerging concepts in the flavinylation of succinate dehydrogenase by Hyung J. Kim; Dennis R. Winge (627-636).
The Succinate Dehydrogenase (SDH) heterotetrameric complex catalyzes the oxidation of succinate to fumarate in the tricarboxylic acid (TCA) cycle and in the aerobic respiratory chains of eukaryotes and bacteria. Essential in this catalysis is the covalently-linked cofactor flavin adenine dinucleotide (FAD) in subunit1 (Sdh1) of the SDH enzyme complex. The mechanism of FAD insertion and covalent attachment to Sdh1 is unknown. Our working concept of this flavinylation process has relied mostly on foundational works from the 1990s and by applying the principles learned from other enzymes containing a similarly linked FAD. The discovery of the flavinylation factor Sdh5, however, has provided new insight into the possible mechanism associated with Sdh1 flavinylation. This review focuses on encapsulating prior and recent advances towards understanding the mechanism associated with flavinylation of Sdh1 and how this flavinylation process affects the overall assembly of SDH. This article is part of a Special Issue entitled: Respiratory complex II: Role in cellular physiology and disease.► The mechanism of FAD covalent attachment to Sdh1 has been a long-standing question. ► The discovery of Sdh5 suggests that Sdh1 flavinylation is a complex, non-autocatalytic process. ► FAD and succinate binding to Sdh1 and its binding to Sdh5 and Sdh2 are important in flavinylation. ► A conceptual model is presented based on prior/current findings in flavinylation/SDH assembly.
Keywords: Succinate dehydrogenase; Flavinylation; FAD; Cofactor; Sdh5; Sdh1;

Prokaryotic assembly factors for the attachment of flavin to complex II by Matthew B. McNeil; Peter C. Fineran (637-647).
Complex II (also known as Succinate dehydrogenase or Succinate–ubiquinone oxidoreductase) is an important respiratory enzyme that participates in both the tricarboxylic acid cycle and electron transport chain. Complex II consists of four subunits including a catalytic flavoprotein (SdhA), an iron–sulphur subunit (SdhB) and two hydrophobic membrane anchors (SdhC and SdhD). Complex II also contains a number of redox cofactors including haem, Fe–S clusters and FAD, which mediate electron transfer from succinate oxidation to the reduction of the mobile electron carrier ubiquinone. The flavin cofactor FAD is an important redox cofactor found in many proteins that participate in oxidation/reduction reactions. FAD is predominantly bound non-covalently to flavoproteins, with only a small percentage of flavoproteins, such as complex II, binding FAD covalently. Aside from a few examples, the mechanisms of flavin attachment have been a relatively unexplored area. This review will discuss the FAD cofactor and the mechanisms used by flavoproteins to covalently bind FAD. Particular focus is placed on the attachment of FAD to complex II with an emphasis on SdhE (a DUF339/SDH5 protein previously termed YgfY), the first protein identified as an assembly factor for FAD attachment to flavoproteins in prokaryotes. The molecular details of SdhE-dependent flavinylation of complex II are discussed and comparisons are made to known cofactor chaperones. Furthermore, an evolutionary hypothesis is proposed to explain the distribution of SdhE homologues in bacterial and eukaryotic species. Mechanisms for regulating SdhE function and how this may be linked to complex II function in different bacterial species are also discussed. This article is part of a Special Issue entitled: Respiratory complex II: Role in cellular physiology and disease.► SdhE is the only accessory protein identified for the attachment of FAD to complex II in bacteria. ► SdhE binds FAD, interacts with, and flavinylates the flavoprotein subunit, SdhA. ► SdhA is unflavinylated in sdhE mutants and complex II is assembled, but inactive. ► SdhE homologues are present in proteobacterial and eukaryotic species and their function is conserved.
Keywords: Flavin adenine dinucleotide; Flavoprotein; Succinate dehydrogenase; sdhA; sdhE; sdh5;

Over a decade has passed since the elucidation of the first X-ray crystal structure of any complex II homolog. In the intervening time, the structures of five additional integral-membrane complex II enzymes and three homologs of the soluble domain have been determined. These structures have provided a framework for the analysis of enzymological studies of complex II superfamily enzymes, and have contributed to detailed proposals for reaction mechanisms at each of the two enzyme active sites, which catalyze dicarboxylate and quinone oxidoreduction, respectively. This review focuses on how structural data have augmented our understanding of catalysis by the superfamily. This article is part of a Special Issue entitled: Respiratory complex II: Role in cellular physiology and disease.Display Omitted► An overview of the structures of complex II superfamily enzymes is presented. ► The contribution of the structures to the development of reaction mechanisms is reviewed. ► Detailed proposals for the function of specific amino acids are discussed.
Keywords: Complex II; Succinate dehydrogenase; Succinate:quinone oxidoreductase; Fumarate reductase; Quinol:fumarate reductase; X-ray crystallography;

Diversity of parasite complex II by Shigeharu Harada; Daniel Ken Inaoka; Junko Ohmori; Kiyoshi Kita (658-667).
Parasites have developed a variety of physiological functions necessary for completing at least part of their life cycles in the specialized environments of surrounding the parasites in the host. Regarding energy metabolism, which is essential for survival, parasites adapt to the low oxygen environment in mammalian hosts by using metabolic systems that are very different from those of the hosts. In many cases, the parasite employs aerobic metabolism during the free-living stage outside the host but undergoes major changes in developmental control and environmental adaptation to switch to anaerobic energy metabolism. Parasite mitochondria play diverse roles in their energy metabolism, and in recent studies of the parasitic nematode, Ascaris suum, the mitochondrial complex II plays an important role in anaerobic energy metabolism of parasites inhabiting hosts by acting as a quinol-fumarate reductase. In Trypanosomes, parasite complex II has been found to have a novel function and structure. Complex II of Trypanosoma cruzi is an unusual supramolecular complex with a heterodimeric iron–sulfur subunit and seven additional non-catalytic subunits. The enzyme shows reduced binding affinities for both substrates and inhibitors. Interestingly, this structural organization is conserved in all trypanosomatids. Since the properties of complex II differ across a wide range of parasites, this complex is a potential target for the development of new chemotherapeutic agents. In this regard, structural information on the target enzyme is essential for the molecular design of drugs. This article is part of a Special Issue entitled: Respiratory complex II: Role in cellular physiology and disease.Display Omitted► Parasite mitochondria play diverse roles in anaerobic metabolism. ► Ascaris suum complex II plays an important role as a quinol-fumarate reductase. ► Complex II of Trypanosoma cruzi is an unusual 12 subunits complex. ► Novel complex II is a potential target for the new chemotherapeutic agents. ► Structural information on the enzyme is essential for the molecular drug design.
Keywords: Complex II; Fumarate respiration; Ascaris suum; Trypanosoma cruzi; Chemotherapy; Drug design;

Defining a direction: Electron transfer and catalysis in Escherichia coli complex II enzymes by Elena Maklashina; Gary Cecchini; Sergei A. Dikanov (668-678).
There are two homologous membrane-bound enzymes in Escherichia coli that catalyze reversible conversion between succinate/fumarate and quinone/quinol. Succinate:ubiquinone reductase (SQR) is a component of aerobic respiratory chains, whereas quinol:fumarate reductase (QFR) utilizes menaquinol to reduce fumarate in a final step of anaerobic respiration. Although, both protein complexes are capable of supporting bacterial growth on either minimal succinate or fumarate media, the enzymes are more proficient in their physiological directions. Here we evaluate factors that may underlie this catalytic bias. This article is part of a Special Issue entitled: Respiratory complex II: Role in cellular physiology and disease.► An overview on the role of the redox properties of Fe–S clusters in the catalysis of complex II enzymes ► Described mechanisms that prevent SQR from efficient fumarate reduction ► The role of polar groups of the quinoid ring of ubiquinone in reactions with complex II
Keywords: Complex II; Succinate:quinone oxidoreductase; Quinol:fumarate reductase; Protein electron transport; Iron sulfur cluster; Quinone binding site;

The di-heme family of respiratory complex II enzymes by C. Roy D. Lancaster (679-687).
The di-heme family of succinate:quinone oxidoreductases is of particular interest, because its members support electron transfer across the biological membranes in which they are embedded. In the case of the di-heme-containing succinate:menaquinone reductase (SQR) from Gram-positive bacteria and other menaquinone-containing bacteria, this results in an electrogenic reaction. This is physiologically relevant in that it allows the transmembrane electrochemical proton potential Δp to drive the endergonic oxidation of succinate by menaquinone. In the case of the reverse reaction, menaquinol oxidation by fumarate, catalysed by the di-heme-containing quinol:fumarate reductase (QFR), evidence has been obtained that this electrogenic electron transfer reaction is compensated by proton transfer via a both novel and essential transmembrane proton transfer pathway (“E-pathway”). Although the reduction of fumarate by menaquinol is exergonic, it is obviously not exergonic enough to support the generation of a Δp. This compensatory “E-pathway” appears to be required by all di-heme-containing QFR enzymes and results in the overall reaction being electroneutral. In addition to giving a brief overview of progress in the characterization of other members of this diverse family, this contribution summarizes key evidence and progress in identifying constituents of the “E-pathway” within the framework of the crystal structure of the QFR from the anaerobic epsilon-proteobacterium Wolinella succinogenes at 1.78 Å resolution. This article is part of a Special Issue entitled: Respiratory complex II: Role in cellular physiology and disease.
Keywords: Atomic model; Fumarate reductase; Membrane protein; Transmembrane electrochemical proton potential; Transmembrane electron transfer; Transmembrane proton transfer;