Sci. Aging Knowl. Environ., 5 February 2003
Vol. 2003, Issue 5, p. pe3
[DOI: 10.1126/sageke.2003.5.pe3]

PERSPECTIVES

Structure-(Dys)function Relationships in Mitochondrial Electron Transport Chain Complex II?

Bruce S. Kristal, and Boris F. Krasnikov

The authors are with the Dementia Research Service of the Burke Medical Research Institute, White Plains, NY 10605, USA (B.S.K. and B.F.K.) and the Departments of Biochemistry and Neuroscience at Weill Medical College of Cornell University, New York, NY 10021, USA (B.S.K.). E-mail: bkristal{at}burke.org (B.S.K).

http://sageke.sciencemag.org/cgi/content/full/sageke;2003/5/pe3

Key Words: succinate dehydrogenase • mitochondria • electron transport • free radical theory of aging • reactive oxygen species

Introduction

The mechanisms of mitochondrial electron transport lead to the production of reactive oxygen species (ROS) as a byproduct (see "The Two Faces of Oxygen"). ROS-mediated oxidative damage to cellular structures and macromolecules has been proposed as one of the driving forces behind the linked processes of aging and age-related diseases (see, for example, Pratic� Review). During electron transfer, single electrons are sometimes inappropriately transferred to oxygen to create ROS, a process referred to as "electron leakage." The major sites of electron leakage have been believed to be complexes I (NADH dehydrogenase) and III (cytochrome bc1) of the electron transport chain, although there is evidence for the involvement of other mitochondrial enzymes. In contrast, complex II (succinate dehydrogenase) has only rarely been associated with electron leakage and subsequent generation of ROS. A new study by Yankovskaya and colleagues (1), described in the 31 January 2003 issue of Science, now reveals the molecular architecture of the Escherichia coli succinate dehydrogenase complex [complex II, succinate:ubiquinone oxidoreductase (SQR)].

The reason(s) for the relative lack of ROS production from complex II under normal conditions, coupled with its purported ability to produce ROS under altered environmental or genetic influences (2), has been unclear. Yankovskaya et al. identify a potential structural basis for this apparent lack of complex II-associated ROS production and also provide an explanation of why mutation of a component of complex II in the short-lived Caenorhabditis elegans mev-1 mutant (see below) might compromise the intrinsic safety mechanism(s) in complex II and lead to enhanced production of ROS.

This perspective briefly reviews the proposed interactions between aging and mitochondrial ROS production, discusses the production of ROS by the mitochondrial electron transport chain, and concludes with a discussion of the implications of the Yankovskaya et al. paper.

Mitochondrial-ROS Interactions

Mitochondria are both important targets and important sources of ROS. It has been proposed that damage to the mitochondrial membranes stimulates further oxidant production (3). This potential positive feedback loop between oxidative stress and mitochondrial dysfunction may lead to a deleterious spiral and eventual mitochondrial collapse and cell death. Proponents of this hypothesis include Harman (4), Miquel (5), and Barja (6). Work from several groups, including Barja and colleagues, has provided evidence that the formation of free radicals (species such as ROS that contain at least one unpaired electron) in mitochondria is more closely associated with life-span than is antioxidant protection or free-radical scavenging (6, 7). These data are consistent with a growing understanding that even if the majority of mitochondrially produced radicals are scavenged by antioxidant enzymes and other mechanisms, several consequences (for example, loss of repiratory efficiency, decreased maximal respiratory capacity, or delay in the recovery response after challenge) follow. This is particularly true in cases where electron leak/ROS generation is increased (for example, by disease). In addition to a loss of efficiency (protons pumped per unit of oxygen consumed) in the process of electron transport as a result of the electron leak and any loss of efficiency related to the scavenging (such as by increased ubiquinol-mediated regeneration of the tocopheroxyl radical; see below), some ROS are likely to escape, especially because even basal levels are not completely scavenged (8).

Electron Transport and Oxidative Phosphorylation

Basic mitochondrial energetics have been expertly reviewed in another SAGE KE article (see Nicholls Perspective). Briefly, the mitochondrial respiratory chain consists of five protein complexes: NADH dehydrogenase (complex I), succinate dehydrogenase [complex II, also part of the tricarboxylic acid cycle (TCA cycle)], cytochrome bc1 complex (complex III), cytochrome c oxidase (complex IV), and the FoF1 ATPase (complex V). The first four components are also referred to collectively as the mitochondrial electron transport chain. Under physiological conditions, electrons carried by NADH or FADH2 (generated by the TCA cycle) generally enter the transport chain either through complex I or complex II, respectively. Electrons are carried through the chain by a variety of carriers, including heme-containing cytochromes, iron-sulfur proteins, and ubiquinone (oxidized coenzyme Q), a small hydrophobic molecule present in the inner mitochondrial membrane. Electron and proton transport by ubiquinone, ubisemiquinone (the one-electron reduction product of ubiquinone), and ubiquinol (the two-electron reduction product) forms the basis of the protonmotive Q-cycle portion of complex III that links complexes I and II to the Rieske iron sulfur protein in complex III (9, 10-14). Quinones (including flavinquinones) also serve as electron carriers in complexes I and II. The energy released during the transfer of electrons from carrier to carrier is used to pump protons from the inner mitochondrial matrix to the intermembrane space at three points in the chain (complexes I, III, and IV). These protons can be used for work (for example, to transport Ca2+) or can be used to generate adenosine triphosphate in the process of oxidative phosphorylation.

Mitochondrial pathways of energy production culminate in the coupled transfer of four electrons (and four protons) to molecular oxygen to form water. This final reaction, catalyzed by cytochrome oxidase, is "safe" in that the coordinate sequential transfer of four single electrons is rarely, if ever, associated with free radical damage. However, reactions earlier in the electron transport chain involve the obligate transfer of unpaired electrons (13), and these sites can generate ROS.

Mitochondrial ROS Production

Mitochondrial ROS production is an obligate byproduct of electron transport. The concept that the electron transport chain is simply a series of controlled free radical reactions is central to understanding the biology and biochemistry of electron transport. The most familiar radical in the electron transport chain is the semiquinone within complex III (13, 15, 16), but complex I also uses a semiquinone radical, and the complex II-III junction also involves a single electron reaction. It has been generally estimated that ~1 to 4% of total oxygen consumed is converted to ROS (8, 17, 18), although these estimates may be 10 times too high (19, 20). This level is increased under some forms of impaired mitochondrial respiration.

Electron leak has been believed to occur predominantly in complexes I and III, and leakage is positively correlated with mitochondrial membrane potential ({Delta}{Psi}), possibly because increased {Delta}{Psi} stabilizes a normally transient semiquinone (complex I, flavinsemiquinone; complex III, ubisemiquinone) (21). At least for complex III, the relationship is nonlinear, with only the highest {Delta}{Psi} values apparently supporting electron leak and subsequent generation of the ROS superoxide (21-23) and its detoxification (dismutation) byproduct hydrogen peroxide (24), a different ROS in isolated mitochondria. ROS generation at complex I is from 20 to 50% of that seen in complex III in liver and kidney mitochondria but may dominate in brain and heart mitochondria [see (8, 20, 25-29)].

Site-Specific Electron Leak: Complex II

Complex II consists of the TCA cycle enzyme succinate dehydrogenase and the accessory factors that couple it to the quinone in complex III. The oxidation of succinate to fumarate transfers a pair of electrons to FAD to make FADH2. These electrons are then passed to a heme-containing protein that transfers them into the Q cycle. Although the oxidation of succinate involves the transfer of two electrons to the ubiquinone/semiubiquinone in complex III, there is evidence that the iron sulfur centers of complex II that serve as intermediates between succinate dehydrogenase and ubiquinone are one-electron carriers. Despite this single-electron transfer, there has been little evidence that complex II is a major source of electron leak and free radical generation under normal physiological conditions.

Nearly all of the evidence for the generation of ROS by complex II is limited by at least one of several concerns: (i) studies did not rule out generation of ROS by reverse electron flow through complex I, (ii) studies did not rule out leakage within complex III, or (iii) leakage caused by inhibition of complex II is proposed (without direct testing) to be caused by leakage at complex II. Possibility (iii) is particularly a problem in experiments on intact cells. Other problems, such as inappropriate controls, methods, or inhibitors, have also contributed to indecisive experiments. In many cases, the authors of the original publications were well aware of the limitations of their data, but subsequent readers and reviewers were not so careful.

In contrast, the mutation of C. elegans mev-1 provides evidence in support of a leak at complex II. mev-1 was originally isolated as a mutant that showed increased sensitivity to the oxidant methyl viologen (paraquat) (30). The mev-1 mutant also showed increased sensitivity to hyperoxia (an excess of oxygen in the system), including a decreased life expectancy when raised at higher oxygen concentrations that is not observed in the wild type (31). The MEV-1 product is homologous to the bovine succinate dehydrogenase cytochrome b560. Although the mev-1 mutation does not affect the succinate dehydrogenase activity of the enzyme or its localization, it does reduce complex II function in electron transport assays (31). This last finding is consistent with a true localization of the defect at complex II-III. Senoo-Matsuda and colleagues furthered this study by providing evidence and an argument for the source of the electrons being at complex II rather than III (2). Further studies may eventually be required, however, as the studies presented in the Senoo-Matsuda paper do not address all of the concerns about proving that leakage occurs at complex II that were raised in the previous paragraph.

The small amount of data that do make a strong case for ROS production in complex II suggest that, under most conditions, complex II does not produce ROS. The mev-1 data suggest that genetic alterations in complex II, or perhaps environmental conditions (based on other literature), can lead to ROS production. The mechanisms underlying these potential differences were unclear, but two recent papers (1, 32) appear to have answered the major questions about mechanisms and nature of ROS formation--or lack thereof--and raised other questions about complex II-mediated ROS formation in aged organisms.

Both studies examined the enzymes involved in the interconversion of succinate and fumarate in E. coli. In eukaryotes, the interconversion of succinate and fumarate is conducted by a single enzyme, succinate dehydrogenase. In contrast, E. coli has both a succinate dehydrogenase (SQR) and a fumarate reductase (QFR). SQR is normally used in aerobic metabolism to convert succinate into fumarate, coupled with the simultaneous reduction of FAD to FADH2. The bacterial enzyme is considered to be well conserved with its eukaryotic counterpart. QFR is normally used in anaerobic metabolism to convert fumarate to succinate, with the concurrent oxidation of FADH2 to FAD. Furthermore, it has previously been shown that QFR can substitute for SQR in complex II but that its actions are associated with ROS formation. This provides a critical scientific advantage of working with the E. coli model: the ability to compare what are essentially two functionally equivalent enzymes that differ primarily in one property of interest--the generation of ROS.

Messner and Imlay: ROS Formation in QFR

In a recent paper appearing in The Journal of Biological Chemistry, Messner and Imlay (32) provide strong biochemical data regarding the mechanisms by which QFR generates ROS. These authors showed that both hydrogen peroxide and superoxide were generated by this enzyme. Superoxide formation was favored by partial enzyme reduction, whereas hydrogen peroxide formation was favored by complete reduction. The researchers also showed that the major species involved in initiating the formation of ROS was the fully reduced FAD moiety, which is particularly solvent accessible in fumarate reductase. These data, coupled with other data discussed in the paper, provide a picture that contrasts sharply with the models of ROS formation in complexes I and III, which appear to be driven by semiquinones. Messner and Imlay further note that the Fe-S cluster potentials in both SQR and QFR pull electrons in the desired direction (that is, toward FAD for fumarate reductase and away in SQR). Comparative experiments show that SQR only releases superoxide. The researchers conclude their "Results" section by noting that, "despite their similar architectures, the electronic differences between Sdh (SQR, succinate dehydrogenase) and Frd (FQR, fumarate reductase) cause quite different autooxidation behaviors." Yankovskaya and colleagues pick up the story at this point, laying out a more detailed architecture that appears to answer the remaining questions.

Yankovskaya et al.: Structure and (Dys)function in Complex II

Yankovskaya and colleagues (1) analyzed the structure of the succinate dehydrogenase complex (which consists of SdhA, SdhB, SdhC, and SdhD subunits) derived from E. coli, and used these data to propose that the critical distinction that underlies the difference in redox metabolism between SQR and QFR [whose structure was previously determined (33)] is in the arrangement of the redox centers (outlined in Fig. 1). In SQR, these centers are arranged in what is essentially a single plane within each monomeric subunit of the overall trimeric structure, with each redox center's edge lying within the limit for physiological electron transfer (Fig. 1). The chain appears linear until a final bifurcation that predisposes electrons to reduce the quinone, but also allows a less frequent reduction of the cytochrome b heme. Understanding the functional consequences of this structural bifurcation may eventually also help contribute to our understanding of entry of electrons into the Q cycle. This heme group can thus pull electrons away from the FAD moiety when the quinone site is unoccupied. This piece of architectural information was unknown when Messner and Imlay wrote their paper, and it is critical to the evolution of the ideas put forth by Yankovskaya et al. In the E. coli SQR, the highest redox potentials are at the cytochrome b heme and the 3Fe-4S cluster, whereas in QFR, the highest potential is in the 2Fe-2S cluster and the FAD moiety. The consequences of this shift in potential are dramatic. Specifically, as calculated and presented in Table 2 of Yankovskaya et al. (Fig. 2), the result is a 50-fold increase in electron occupancy at the FAD site in QFR as compared to SQR when the quinone site is unoccupied. As noted above, Messner and Imlay (32) had previously demonstrated that the primary site of leakage in QFR was the FAD moiety. In a secondary comparison, Yankovskaya et al. note that compounding the quinone deficit with the loss of the cytochrome b heme would increase electron density ninefold at the FAD moiety in SQR, but that there would still be more than fivefold fewer electrons on the FAD in SQR than QFR.



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Fig. 1. Overall structure of E. coli SQR. SdhA, SdhB, SdhC, and SdhD subunits are shown in purple, orange, green, and blue, respectively. FAD is shown in gold and oxaloacetate in green. Heme b and ubiquinone are shown in magenta and yellow. Fe and S atoms of FeS clusters are red and yellow, respectively. Cardiolipin is shown in gray. The SQR monomer is viewed parallel to the membrane. The center-to-center and edge-to-edge (in parentheses) distances between redox centers in E. coli SQR are also shown. [Figure and legend are from (1)]

 


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Fig. 2. Electron distribution among the redox centers of E. coli SQR and QFR. *The distribution of two electrons was calculated assuming an equilibrium distribution among independent redox centers of given reduction potentials at 298 K. One-electron reduction potentials of the flavin quinone/semiquinone and semiquinone/hydroquinone are treated as the same. For details, see (1) and reference 16 therein. {dagger} The value for bovine SQR is used. [Figure and legend are from (1)]

 
Several specific amino acid residues also are implicated in protecting SQR function and preventing ROS formation. Yankovskaya et al. report that a residue in subunit SdhB (Cys B154) is hydrogen-bonded to the thiol group of a [4Fe-4S] ligand of Cys B152. This bond is conserved in SQRs but not in QFR, and Yankovskaya et al. cite evidence that this might be related to the redox balance across the chain. The residues in the quinone-binding site are conserved from bacteria to mammals. Mutations in SQR are associated with both pheochromocytomas and paragangliomas (34). Mutation of the mammalian equivalent of Pro B160 is associated with pheochromocytomas. The mev-1 phenotype results from a mutation in the C. elegans equivalent of Ile C28. These observations suggest that appropriate stabilization of the quinone pocket is critical to prevent dysfunction.

Abnormalities in SDH and Its Environment

Thus, the work of Yankovskaya and colleagues clearly provides a structural basis for the ability of succinate dehydrogenase to carry out its intended reactions without, under normal conditions, generating large quantities of ROS. This work, however, also suggests the specter of the potential for complex II to generate ROS under the less ideal conditions in the aging animal. In this respect, the Yankovskaya paper provides direct information for one case of concern, the absence of the quinone. Quinone availability may be decreased as a result of aging-associated decreases in quinone levels (which is controversial) or as a result of delayed transit times through the membrane caused by a decrease in fluidity subsequent to lipid peroxidation damage [(35, 36) and see Pratic� Review]. Under otherwise normal conditions, only a minimal increase in electron density at the FAD moiety would be expected, leading to an expectation of low ROS formation. Similarly, disproportionate representation of other electron transport proteins (for example, complexes I, III, or IV), such as might occur as a consequence of mitochondrial DNA mutations or exposure to damaging agents, would seem unlikely to accelerate ROS formation in the absence of other changes that destabilize complex II directly. In these cases, the structural safeguards work. In contrast, coupling decreased quinine availability with a decrease in the cytochrome b heme clearly increases electron density at FAD, suggesting a potential 10-fold increase in ROS formation. Similarly, oxidative damage to the Fe-S clusters, for example, might also increase electron density at the FAD moiety and accelerate ROS formation. Likewise, changes in overall protein structure as a result of increased damage, altered membrane properties, aging-related decreases in the concentration of cardiolipin (a phospholipid in mitochondrial membranes that is important for mitochondrial function and is very sensitive to oxidative damage), altered solvent exposure, decreased replacement, or increased mitochondrial mutations with age might partially alter (unfold?) the structure, altering the thermodynamic balances that stabilize the system and keep electrons away from the FAD. Thus, as much as the structure of succinate dehydrogenase predicts its function, it may also predict dysfunction in the aged organism or under adverse conditions. Clearly, the presentation of the molecular architecture of succinate dehydrogenase opens another aspect of mitochondrial biology and its influence on aging processes.


February 5, 2003
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Citation: B. S. Kristal, B. F. Krasnikov, Structure-(Dys)function Relationships in Mitochondrial Electron Transport Chain Complex II? Science's SAGE KE (5 February 2003), http://sageke.sciencemag.org/cgi/content/full/sageke;2003/5/pe3








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