Key points are not available for this paper at this time.
Neither the route of electron transport nor the sites or mechanism of superoxide production in mitochondrial complex I has been established. We examined the rates of superoxide generation (measured as hydrogen peroxide production) by rat skeletal muscle mitochondria under a variety of conditions. The rate of superoxide production by complex I during NADH-linked forward electron transport was less than 10% of that during succinate-linked reverse electron transport even when complex I was fully reduced by pyruvate plus malate in the presence of the complex III inhibitor, stigmatellin. This asymmetry was not explained by differences in protonmotive force or its components. However, when inhibitors of the quinone-binding site of complex I were added in the presence of ATP to generate a pH gradient, there was a rapid rate of superoxide production by forward electron transport that was as great as the rate seen with reverse electron transport at the same pH gradient. These observations suggest that quinone-binding site inhibitors can make complex I adopt the highly radical-producing state that occurs during reverse electron transport. Despite complete inhibition of NADH: ubiquinone oxidoreductase activity in each case, different classes of quinone-binding site inhibitor (rotenone, piericidin, and high concentrations of myxothiazol) gave different rates of superoxide production during forward electron transport (the rate with myxothiazol was twice that with rotenone) suggesting that the site of rapid superoxide generation by complex I is in the region of the ubisemiquinone-binding sites and not upstream at the flavin or low potential FeS centers. Neither the route of electron transport nor the sites or mechanism of superoxide production in mitochondrial complex I has been established. We examined the rates of superoxide generation (measured as hydrogen peroxide production) by rat skeletal muscle mitochondria under a variety of conditions. The rate of superoxide production by complex I during NADH-linked forward electron transport was less than 10% of that during succinate-linked reverse electron transport even when complex I was fully reduced by pyruvate plus malate in the presence of the complex III inhibitor, stigmatellin. This asymmetry was not explained by differences in protonmotive force or its components. However, when inhibitors of the quinone-binding site of complex I were added in the presence of ATP to generate a pH gradient, there was a rapid rate of superoxide production by forward electron transport that was as great as the rate seen with reverse electron transport at the same pH gradient. These observations suggest that quinone-binding site inhibitors can make complex I adopt the highly radical-producing state that occurs during reverse electron transport. Despite complete inhibition of NADH: ubiquinone oxidoreductase activity in each case, different classes of quinone-binding site inhibitor (rotenone, piericidin, and high concentrations of myxothiazol) gave different rates of superoxide production during forward electron transport (the rate with myxothiazol was twice that with rotenone) suggesting that the site of rapid superoxide generation by complex I is in the region of the ubisemiquinone-binding sites and not upstream at the flavin or low potential FeS centers. It is well established that the mitochondrial electron transport chain produces superoxide ( O2−˙), as the result of single electron leaks to oxygen during electron transport from reduced substrates to complex IV (1Turrens J.F. J. Physiol. (Lond.). 2003; 552: 335-344Crossref Scopus (3657) Google Scholar). Superoxide is converted into hydrogen peroxide by the action of manganese superoxide dismutase (SOD) 1The abbreviations used are: SOD, superoxide dismutase; ROS, reactive oxygen species; Q, ubiquinone; PHPA, p-hydroxyphenylacetic acid; TPMP, triphenylmethylphosphonium. in the mitochondrial matrix or by the action of copper/zinc SOD in the cytosol. If superoxide is not removed from the mitochondrial matrix, as in the case of manganese SOD nullizygous mice, severe pathologies arise, and the life-span is curtailed to about 10 days (2Li Y. Huang T.T. Carlson E.J. Melov S. Ursell P.C. Olson J.L. Noble L.J. Yoshimura M.P. Berger C. Chan P.H. Wallace D.C. Epstein C.J. Nat. Genet. 1995; 11: 376-381Crossref PubMed Scopus (1462) Google Scholar). If superoxide is not removed from the cytosol, as in the case of copper/zinc SOD nullizygous mice, the effects are not lethal, although an increase in sensitivity to oxidative stress is apparent (3Ho Y.S. Gargano M. Cao J. Bronson R.T. Heimler I. Hutz R.J. J. Biol. Chem. 1998; 273: 7765-7769Abstract Full Text Full Text PDF PubMed Scopus (280) Google Scholar). Thus there is intense interest in superoxide and the other reactive oxygen species (ROS) it gives rise to (such as hydrogen peroxide and hydroxyl radical), as ROS clearly play a role in a variety of pathological disorders and perhaps aging (4Halliwell B. Gutteridge J.M.C. Free Radicals in Biology and Medicine. Oxford University Press Inc., New York1999Google Scholar, 5Cadenas E. Davies K.J. Free Radic. Biol. Med. 2000; 29: 222-230Crossref PubMed Scopus (2409) Google Scholar). The sites of superoxide production within the mitochondrial electron transport chain in vitro have been localized to complexes I and III (6Raha S. Robinson B.H. Trends Biochem. Sci. 2000; 25: 502-508Abstract Full Text Full Text PDF PubMed Scopus (907) Google Scholar). Complex I produces superoxide to the matrix side of the mitochondrial membrane exclusively, whereas complex III appears to produce superoxide to both the matrix and intermembrane space in roughly equal amounts (7St-Pierre J. Buckingham J.A. Roebuck S.J. Brand M.D. J. Biol. Chem. 2002; 277: 44784-44790Abstract Full Text Full Text PDF PubMed Scopus (1240) Google Scholar, 8Han D. Williams E. Cadenas E. Biochem. J. 2001; 353: 411-416Crossref PubMed Scopus (488) Google Scholar, 9Miwa S. St-Pierre J. Partridge L. Brand M.D. Free Radic. Biol. Med. 2003; 35: 938-948Crossref PubMed Scopus (267) Google Scholar). The relative importance of each complex to total superoxide production is debated; during reverse electron transport from succinate to NAD, complex I produces superoxide at very high rates (10Turrens J.F. Boveris A. Biochem. J. 1980; 191: 421-427Crossref PubMed Scopus (1367) Google Scholar, 11Liu Y. Fiskum G. Schubert D. J. Neurochem. 2002; 80: 780-787Crossref PubMed Scopus (987) Google Scholar, 12Kushnareva Y. Murphy A.N. Andreyev A. Biochem. J. 2002; 368: 545-553Crossref PubMed Scopus (548) Google Scholar, 13Hansford R.G. Hogue B.A. Mildaziene V. J. Bioenerg. Biomembr. 1997; 29: 89-95Crossref PubMed Scopus (398) Google Scholar, 14Votyakova T.V. Reynolds I.J. J. Neurochem. 2001; 79: 266-277Crossref PubMed Scopus (511) Google Scholar, 15Han D. Canali R. Rettori D. Kaplowitz N. Mol. Pharmacol. 2003; 64: 1136-1144Crossref PubMed Scopus (181) Google Scholar), but the physiological relevance of reverse electron transport in unclear. During forward electron transport, however (which is clearly physiological), both complexes produce superoxide at relatively low rates, unless inhibitors such as rotenone (for complex I) or antimycin A (for complex III) are present. Under these inhibited conditions with forward electron transport (which are not physiological) the superoxide production rates are relatively high. Whatever the relative importance of the complexes to total superoxide production in vivo, compared with complex III, very little is known about the mechanism of complex I superoxide production. In mitochondria, superoxide is produced by the single electron reduction of oxygen by an electron carrier within the electron transport chain. In complex III the electron carriers are cytochromes bL, bH and c1, the Rieske iron-sulfur center, and the semiquinones at centers “i” and “o.” The main reductant of oxygen to produce superoxide at complex III has been identified as the semiquinone at center o, consistent with the Q cycle mechanism of the complex (16Turrens J.F. Alexandre A. Lehninger A.L. Arch. Biochem. Biophys. 1985; 237: 408-414Crossref PubMed Scopus (1073) Google Scholar). In complex I, the electron carriers are the flavin, the iron-sulfur centers N1a, N1b, N2, N3, N4, N5, and an unknown number of semiquinones (17Friedrich T. Biochim. Biophys. Acta. 1998; 1364: 134-146Crossref PubMed Scopus (180) Google Scholar). The reductant of oxygen to produce superoxide in this enzyme is not known, and published reports are highly conflicting. On thermodynamic grounds, center N1a (12Kushnareva Y. Murphy A.N. Andreyev A. Biochem. J. 2002; 368: 545-553Crossref PubMed Scopus (548) Google Scholar) and the flavin (18Kudin A.P. Bimpong-Buta N.Y. Vielhaber S. Elger C.E. Kunz W.S. J. Biol. Chem. 2004; 279: 4127-4135Abstract Full Text Full Text PDF PubMed Scopus (430) Google Scholar) were suggested as the main superoxide producing sites. Based on inhibitor studies, the flavin (11Liu Y. Fiskum G. Schubert D. J. Neurochem. 2002; 80: 780-787Crossref PubMed Scopus (987) Google Scholar, 19Young T.A. Cunningham C.C. Bailey S.M. Arch. Biochem. Biophys. 2002; 405: 65-72Crossref PubMed Scopus (111) Google Scholar), center N2 (20Genova M.L. Ventura B. Giuliano G. Bovina C. Formiggini G. Parenti Castelli G. Lenaz G. FEBS Lett. 2001; 505: 364-368Crossref PubMed Scopus (263) Google Scholar) and the iron-sulfur proteins and semiquinones in general (21Herrero A. Barja G. J. Bioenerg. Biomembr. 2000; 32: 609-615Crossref PubMed Scopus (139) Google Scholar) were suggested as sites of superoxide production. It is feasible that all these sites produce superoxide and that production rates by different sites are tissue or condition specific. We recently demonstrated that superoxide production rates by complex I during reverse electron transport are highly dependent on the pH gradient (ΔpH) across the mitochondrial inner membrane (22Lambert A.J. Brand M.D. Biochem. J. 2004; 382: PubMed Scopus Google Scholar). of complex I ROS production used conditions in the pH gradient was or very the site of superoxide production by the It has been suggested that the main site of superoxide production within complex I is a semiquinone (6Raha S. Robinson B.H. Trends Biochem. Sci. 2000; 25: 502-508Abstract Full Text Full Text PDF PubMed Scopus (907) Google Scholar). superoxide production rates by complex I during reverse electron are than during forward electron this have conditions in it is suggest that the site of superoxide production in complex I is the quinone-binding it is a A was a from of other were from of Superoxide from skeletal muscle of and were by as A.J. Brand M.D. Biochim. Biophys. Acta. PubMed Scopus Google Scholar). Superoxide production rate was by of hydrogen peroxide generation by of of p-hydroxyphenylacetic to the reduction of by of mitochondrial were at in at PHPA, superoxide dismutase and The was by of the increase in at an of and of was on a were (7St-Pierre J. Buckingham J.A. Roebuck S.J. Brand M.D. J. Biol. Chem. 2002; 277: 44784-44790Abstract Full Text Full Text PDF PubMed Scopus (1240) Google Scholar), and known amounts of were used to the rate of production in mitochondrial all the superoxide from complex I is on the matrix side of the inner membrane and converted by to leaks and is in the (7St-Pierre J. Buckingham J.A. Roebuck S.J. Brand M.D. J. Biol. Chem. 2002; 277: 44784-44790Abstract Full Text Full Text PDF PubMed Scopus (1240) Google Scholar). in the (such as myxothiazol and of the with all conditions was to the rates of production. of membrane was an to as M.D. C.E. A Scholar). muscle mitochondria were under the same conditions as superoxide production at in with PHPA, and The was by of to The was by of and was the state The of protonmotive was as the in was converted to of each the was added to to the and in the were as M.D. C.E. A Scholar), on the that in to that were and pH that were of I activity was by the of with as an electron was at and of and under and conditions to used of and to with complex I, the mitochondria were by to The concentrations of piericidin, and myxothiazol to inhibition of complex I were by are as with the number of mitochondrial The of differences was by were to of Superoxide by Complex I during and of was to production of superoxide during forward and reverse electron transport by complex I. in with pyruvate malate as the rate of production from the electron transport chain was A rate was of forward electron transport malate succinate as the rate of superoxide production was and was localized at complex I during reverse electron transport (22Lambert A.J. Brand M.D. Biochem. J. 2004; 382: PubMed Scopus Google Scholar). The high rate of superoxide production during reverse electron transport into complex I is very to the pH gradient across the inner mitochondrial membrane (22Lambert A.J. Brand M.D. Biochem. J. 2004; 382: PubMed Scopus Google Scholar), of to by the of inhibited superoxide production was in mitochondria succinate and pyruvate malate the differences in superoxide production forward and reverse electron transport are not to differences in not superoxide production rate with pyruvate malate that with forward electron transport, has on superoxide production rate under these of and under malate from pyruvate malate from pyruvate from pyruvate from pyruvate malate rotenone malate from pyruvate from pyruvate from pyruvate malate from pyruvate from pyruvate malate from pyruvate from pyruvate from pyruvate malate myxothiazol from pyruvate from pyruvate from pyruvate malate from pyruvate from pyruvate from pyruvate malate from pyruvate from pyruvate malate from pyruvate from pyruvate from pyruvate malate malate antimycin from pyruvate from pyruvate from pyruvate malate antimycin A from pyruvate from pyruvate from pyruvate in a It that the complex I site is reduced during reverse electron transport, when are into the complex the high perhaps the high ubiquinone reduction by succinate than it is during forward electron transport, when a little I) and when the ubiquinone this added the complex I inhibitors piericidin, or to the complex to fully reduced by from pyruvate is a center inhibitor of complex III, but at high concentrations it is an inhibitor of complex I (20Genova M.L. Ventura B. Giuliano G. Bovina C. Formiggini G. Parenti Castelli G. Lenaz G. FEBS Lett. 2001; 505: 364-368Crossref PubMed Scopus (263) Google Scholar, M. Biochim. Biophys. Acta. 1998; 1364: PubMed Scopus Google Scholar). of of these inhibitors increase production from pyruvate with myxothiazol the by rotenone The differences inhibitors were not to different of inhibition of complex that superoxide production was each inhibitor, and that each inhibition of oxidoreductase activity at the However, even with production rates were of seen with reverse electron transport, the reduction state of sites upstream of the sites these inhibitors in complex I to the in superoxide production reverse and forward electron transport but fully of complex I oxidoreductase activity by piericidin, and conditions are the same as of on mitochondrial Complex I activity was as at inhibitor It that the main site of superoxide production from complex I is the site If this site with inhibitors (rotenone, piericidin, or high concentrations of myxothiazol) superoxide production during forward electron transport, and the high rates seen with succinate this a condition is in the site within complex I is fully reduced with forward electron transport but to this condition to a low of that center of complex III is The of myxothiazol to fully complex III in was but this inhibited complex I activity by about the sites were not fully at this relatively low myxothiazol under the conditions center inhibitor of complex III is M. A. M. E. R. Lenaz G. Biochem. Biophys. PubMed Scopus Google Scholar), at not complex I activity at all but complex III, as was We the effects of and other different of substrates and inhibitors that produce an site but reduced complex I during forward electron the are in The other condition was pyruvate malate plus reduction of all complexes upstream of complex The other condition pyruvate malate plus antimycin A (which gives complex I superoxide plus superoxide production from complex III) the rate with succinate plus rotenone plus antimycin A (which gives superoxide from complex III of the conditions the rate of superoxide production by complex I with forward electron transport to the rates seen with succinate In the presence of the rate of superoxide production was less than 10% of the rate during reverse electron transport with succinate seen in a fully reduced and site with forward electron transport is not to high rates of superoxide production by complex I. The of on Superoxide during the conditions of pyruvate malate inhibitor in and are I) there is by the electron transport chain. production by complex I is to during reverse electron transport (22Lambert A.J. Brand M.D. Biochem. J. 2004; 382: PubMed Scopus Google Scholar), the in superoxide production rate forward and reverse electron by the of during inhibited forward electron The effects of were of added ATP to produce and in ATP rates of production with all complex I and these were by of to In the presence of pyruvate malate plus myxothiazol and was about 10 and the rate of production was about is the same as the rate by reverse electron transport from succinate at the same (22Lambert A.J. Brand M.D. Biochem. J. 2004; 382: PubMed Scopus Google Scholar). The in production seen of ATP were when was in the that the effects of ATP were by the In of these that ATP by succinate the rate of production was high when succinate was added in the presence of pyruvate malate and rotenone or with pyruvate malate plus or antimycin A with ATP are in It can seen that of a pH gradient not generation of superoxide at high rates in the of Q site a site in the presence of during forward electron transport is not to generate the amounts of superoxide seen during reverse electron transport. However, complex I with its site inhibited by myxothiazol to a by or rotenone) in the presence of during forward electron transport is to generate superoxide at the same rate as it during reverse electron transport from succinate in the of Q site The of pH on Superoxide during the (22Lambert A.J. Brand M.D. Biochem. J. 2004; 382: PubMed Scopus Google Scholar), that the of on production in the presence of pyruvate and ATP was not to in pH the rate of production was in the of than in its superoxide generation during reverse electron transport, superoxide generation during forward electron transport under these conditions is dependent on In with (10Turrens J.F. Boveris A. Biochem. J. 1980; 191: 421-427Crossref PubMed Scopus (1367) Google Scholar, 11Liu Y. Fiskum G. Schubert D. J. Neurochem. 2002; 80: 780-787Crossref PubMed Scopus (987) Google Scholar, 12Kushnareva Y. Murphy A.N. Andreyev A. Biochem. J. 2002; 368: 545-553Crossref PubMed Scopus (548) Google Scholar, 13Hansford R.G. Hogue B.A. Mildaziene V. J. Bioenerg. Biomembr. 1997; 29: 89-95Crossref PubMed Scopus (398) Google Scholar, 14Votyakova T.V. Reynolds I.J. J. Neurochem. 2001; 79: 266-277Crossref PubMed Scopus (511) Google Scholar, 15Han D. Canali R. Rettori D. Kaplowitz N. Mol. Pharmacol. 2003; 64: 1136-1144Crossref PubMed Scopus (181) Google Scholar), that superoxide production by complex I during reverse electron transport is compared with forward electron transport under conditions. This asymmetry of superoxide production by complex I has not been in and of it has been in the We superoxide production by complex I and under conditions can complex I produce superoxide during forward electron transport at the high rates seen during reverse electron transport in mitochondria other can the asymmetry and site in complex I the of the of of Superoxide by of that a pH gradient across the mitochondrial inner membrane during forward and or reverse and A.J. Brand M.D. Biochem. J. 2004; 382: PubMed Scopus Google Scholar) electron is high rates of superoxide production. The pH gradient can by by the case of or by ATP the the electron transport chain is that a relatively reduced complex I a but is not high superoxide generation During reverse electron transport an high reduction state is by the high from succinate into complex I. However, with forward electron transport, a reduced complex I was high superoxide rates have been with pyruvate malate plus or rotenone antimycin This was not the even when ATP was added to generate the superoxide production rates low under these conditions compared with the rates seen with have that Q site inhibition is high rates of superoxide production by complex I during forward electron transport. in the presence of piericidin, or myxothiazol was the superoxide production rate high with forward electron transport Q site inhibitors fully inhibited oxidoreductase but myxothiazol was at superoxide production than piericidin, in was than This appears to the case with complex In its complex III produces superoxide at low rates, but in the presence of antimycin A the rate (7St-Pierre J. Buckingham J.A. Roebuck S.J. Brand M.D. J. Biol. Chem. 2002; 277: 44784-44790Abstract Full Text Full Text PDF PubMed Scopus (1240) Google Scholar, 11Liu Y. Fiskum G. Schubert D. J. Neurochem. 2002; 80: 780-787Crossref PubMed Scopus (987) Google Scholar, 13Hansford R.G. Hogue B.A. Mildaziene V. J. Bioenerg. Biomembr. 1997; 29: 89-95Crossref PubMed Scopus (398) Google Scholar, 15Han D. Canali R. Rettori D. Kaplowitz N. Mol. Pharmacol. 2003; 64: 1136-1144Crossref PubMed Scopus (181) Google Scholar). During forward electron transport, complex I produces superoxide at very low rates in its but the rate can increase in the presence of Q site are in with a on superoxide production in (20Genova M.L. Ventura B. Giuliano G. Bovina C. Formiggini G. Parenti Castelli G. Lenaz G. FEBS Lett. 2001; 505: 364-368Crossref PubMed Scopus (263) Google Scholar). to generate forward electron transport, a very low superoxide production rate was This rate by about when was used to center of complex in rate were seen in the presence of complex I Q site and from it is these rates have been even in the presence of the conditions that the asymmetry of superoxide production forward and reverse electron transport are very specific. The asymmetry is not to differences in the state of complex I or differences in protonmotive force or its components. rates of superoxide in the presence of were with the enzyme during reverse electron transport (22Lambert A.J. Brand M.D. Biochem. J. 2004; 382: PubMed Scopus Google Scholar) or in the presence of Q site inhibitors during forward electron transport. The of these observations is that there is a state of complex I that to high superoxide and this state can during reverse electron transport, or during forward electron transport when an inhibitor the The that different rates of superoxide production were with the different Q site inhibitors is consistent with the of or classes of complex I inhibitor with different of in a M. Biochim. Biophys. Acta. 1998; 1364: PubMed Scopus Google Scholar, J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). of of these sites by an inhibitor superoxide production by the with oxygen of reductant within the Q site (such as a or within complex I. of Superoxide by Complex sites in complex I generate superoxide at high If the main or site of the high superoxide production in the presence of ATP is upstream of the site from centers N1a, N1b, N3, N4, N5, or a chain of electron of Q site inhibitor result in the same rate of superoxide production. This was not the different rotenone) in the rate of superoxide production from pyruvate malate in both the and presence of In sites upstream of Q generate the production rates from complex I with the Q site inhibitors and with or antimycin A. This was clearly not the case We that the sites upstream of Q produce superoxide at low rates compared with the Q site as in reports (11Liu Y. Fiskum G. Schubert D. J. Neurochem. 2002; 80: 780-787Crossref PubMed Scopus (987) Google Scholar, 12Kushnareva Y. Murphy A.N. Andreyev A. Biochem. J. 2002; 368: 545-553Crossref PubMed Scopus (548) Google Scholar, A.P. Bimpong-Buta N.Y. Vielhaber S. Elger C.E. Kunz W.S. J. Biol. Chem. 2004; 279: 4127-4135Abstract Full Text Full Text PDF PubMed Scopus (430) Google Scholar, 19Young T.A. Cunningham C.C. Bailey S.M. Arch. Biochem. Biophys. 2002; 405: 65-72Crossref PubMed Scopus (111) Google Scholar, M.L. Ventura B. Giuliano G. Bovina C. Formiggini G. Parenti Castelli G. Lenaz G. FEBS Lett. 2001; 505: 364-368Crossref PubMed Scopus (263) Google Scholar) suggest that these upstream sites are complex I superoxide production. It is to the from different as the of mitochondrial and ROS and all However, consistent appears to that all of these used conditions in was (the mitochondria or were or low to the presence of in the (22Lambert A.J. Brand M.D. Biochem. J. 2004; 382: PubMed Scopus Google superoxide production was not in these studies, and the site of high superoxide production the sites of superoxide production but not to the site of complex I superoxide production complex III superoxide at high rates when antimycin A is present. This is consistent with the Q cycle and is explained by the of a semiquinone at center of the complex that oxygen to superoxide J.F. 1997; PubMed Scopus Google Scholar). perhaps the Q site inhibitors superoxide production by complex I Q in this complex and that the reductant of oxygen to produce superoxide is a The mechanism of complex I but to the Q cycle in complex III have been C.C. T. Biochim. Biophys. Acta. 1998; 1364: PubMed Scopus Google Scholar). have been suggested that are consistent with Q in the enzyme Biochim. Biophys. Acta. 1997; PubMed Scopus Google Scholar). within the Q site superoxide have at species within complex I, and and very semiquinone T. S. T. Biochim. Biophys. Acta. 2000; PubMed Scopus Google Scholar, T. FEBS Lett. 1995; PubMed Scopus Google Scholar, S. L. T. C. T. J. Bioenerg. Biomembr. 2002; PubMed Scopus Google Scholar). If there is a Q cycle mechanism in complex I, as well as the site there at reduction and of complex I different semiquinone reduction sites and site (6Raha S. Robinson B.H. Trends Biochem. Sci. 2000; 25: 502-508Abstract Full Text Full Text PDF PubMed Scopus (907) Google Scholar, Biochim. Biophys. Acta. 1997; PubMed Scopus Google Scholar). classes of inhibitor have been to semiquinone species in a M. Biochim. Biophys. Acta. 1998; 1364: PubMed Scopus Google Scholar, J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). these sensitivity to superoxide production is very to the reductant of oxygen in complex I. If high sensitivity to In both rotenone and the superoxide production from a of superoxide production at the semiquinone in of the Q sites of complex I that is consistent with the observations and (22Lambert A.J. Brand M.D. Biochem. J. 2004; 382: PubMed Scopus Google Scholar). Superoxide as a to the of Complex (22Lambert A.J. Brand M.D. Biochem. J. 2004; 382: PubMed Scopus Google Scholar), of the the mechanism of complex I has is the of Superoxide production by complex I is an of the of a in complex I and is to It is that this is a semiquinone and in the as it is We that superoxide production by complex I a to into complex I. We and Buckingham
Lambert et al. (Fri,) studied this question.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: