Differential effects of complex II on mitochondrial ROS production and their relation to cardioprotective pre- and postconditioning

In the paper

“Importantly, the modulation of mitochondrial ROS production was independent of K + -ions, indicating that a putative mitoK ATP channel was not involved.”

In the paper

“In addition, similar atpenin A5 concentrations stimulated the superoxide production at the Q o site of antimycin A inhibited complex III, which may represent the source of 'signaling ROS' during ischemic and pharmacological preconditioning [15].”

What the sources say

• Not checked yetcites [15] 15. S. Dröse, P.J. Hanley, U. Brandt, Ambivalent effects of diazoxide on mitochondrial ROS production at respiratory chain complexes I and III, Biochim. Biophys. Acta 1790 (2009) 558-565. source

In the paper

“However, some mutations in complex II subunits that have been linked to specific forms of cancer or neurodegeneration can lead to an increased ROS generation (reviewed in [12][13][14]).”

What the sources say

• Not checked yetcites [12][13][14]

In the paper

“The respiratory chain provides the main portion of ATP in eukaryotic cells, but is also a major source of reactive oxygen species (ROS) [2][3][4][5][6].”

What the sources say

• Not checked yetcites [2][3][4][5][6]

In the paper

“Mitochondrial complex II (succinate:ubiquinone oxidoreductase; succinate dehydrogenase, SDH) oxidizes succinate to fumarate and reduces ubiquinone, thereby creating a direct link between the tricarboxylic acid (TCA) cycle (also known as citric acid or Krebs cycle) and the respiratory chain [1] (Fig. 1).”

What the sources say

• Not checked yetcites [1] 1. G. Cecchini, Function and structure of complex II of the respiratory chain, Annu. Rev. Biochem. 72 (2003) 77-109. source

In the paper

“Within the respiratory chain, complexes I (NADH:ubiquinone oxidoreductase) and III (ubiquinol:cytochrome c oxidoreductase; cytochrome bc 1 complex) are generally regarded as the main ROS sources, while the contribution of intact complex II seems to be negligible [3][4][5][6].”

What the sources say

• Not checked yetcites [3][4][5][6]

In the paper

“This seems to be especially the case for mutations in complex II subunits C and D located in the vicinity of the Qp site that have been associated with specific forms of cancer such as hereditary paragangliomas and pheochromocytomas (overview in [13,14,36]) and in SdhA that can cause Leigh syndrome, a progressive neurodegenerative disease [14,94].”

What the sources say

• Not checked yetcites [13] 13. C. Bardella, P.J. Pollard, I. Tomlinson, SDH mutations in cancer, Biochim. Biophys. Acta 1807 (2011) 1432-1443. source
• Not checked yetcites [14] 14. T.M. Iverson, E. Maklashina, G. Cecchini, Structural basis for malfunction in com- plex II, J. Biol. Chem. 287 (2012) 35430-35438. source
• Not checked yetcites [36] 36. S.J. Ralph, R. Moreno-Sanchez, J. Neuzil, S. Rodriguez-Enriquez, Inhibitors of suc- cinate: quinone reductase/complex II regulate production of mitochondrial re- active oxygen species and protect normal cells from ischemic damage but induce specific cancer cell death, Pharm. Res. 28 (2011) 2695-2730. source
• Not checked yetcites [94] 94. B.A. Ackrell, Cytopathies involving mitochondrial complex II, Mol. Aspects Med. 23 (2002) 369-384. source

In the paper

“This increased succinate pool under hypoxia might be supplied either from glutamate through α-ketoglutarate by transamination [76,77] or by a partial reversal of the TCA cycle from malate through fumarate, which requires that complex II would become a fumarate reductase under hypoxia [36,79].”

What the sources say

• Not checked yetcites [76] 76. R.J. Wiesner, P. Rosen, M.K. Grieshaber, Pathways of succinate formation and their contribution to improvement of cardiac-function in the hypoxic rat-heart, Biochem. Med. Metab. Biol. 40 (1988) 19-34. source
• Not checked yetcites [77] 77. R.J. Wiesner, A. Deussen, M. Borst, J. Schrader, M.K. Grieshaber, Glutamate degra- dation in the ischemic dog heart -contribution to anaerobic energy-production, J. Mol. Cell. Cardiol. 21 (1989) 49-59. source
• Not checked yetcites [36] 36. S.J. Ralph, R. Moreno-Sanchez, J. Neuzil, S. Rodriguez-Enriquez, Inhibitors of suc- cinate: quinone reductase/complex II regulate production of mitochondrial re- active oxygen species and protect normal cells from ischemic damage but induce specific cancer cell death, Pharm. Res. 28 (2011) 2695-2730. source
• Not checked yetcites [79] 79. C. Hohl, R. Oestreich, P. Rosen, R. Wiesner, M. Grieshaber, Evidence for succinate production by reduction of fumarate during hypoxia in isolated adult-rat heart-cells, Arch. Biochem. Biophys. 259 (1987) 527-535. source

In the paper

“E. coli SQR exclusively produces superoxide.In contrast, E. coli QFR produces mainly superoxide at lower succinate concentrations and comparably more hydrogen peroxide at higher substrate concentrations [101].”

What the sources say

• Not checked yetcites [101] 101. K.R. Messner, J.A. Imlay, Mechanism of superoxide and hydrogen peroxide for- mation by fumarate reductase, succinate dehydrogenase, and aspartate oxidase, J. Biol. Chem. 277 (2002) 42563-42571. source

In the paper

“They proposed a mechanism for ROS production by complex II that relies upon the occupancy of the carboxylate binding site and the reduction state of the enzyme, i.e.ROS are only generated when the flavin is reduced and the carboxylate binding site is not occupied.”

What the sources say

• Not checked yetcites [37] 37. C.L. Quinlan, A.L. Orr, I.V. Perevoshchikova, J.R. Treberg, B.A. Ackrell, M.D. Brand, Mitochondrial complex II can generate reactive oxygen species at high rates in both the forward and reverse reactions, J. Biol. Chem. 287 (2012) 27255-27264. source

In the paper

“Furthermore, both enzymes showed maximal rates of ROS at intermediate succinate concentrations between 0.1 and 1 mM and decreased rates at lower and higher substrate concentration, which resembles the dependence found later for mammalian [37] and nematode [100] complex II.”

What the sources say

• Not checked yetcites [37] 37. C.L. Quinlan, A.L. Orr, I.V. Perevoshchikova, J.R. Treberg, B.A. Ackrell, M.D. Brand, Mitochondrial complex II can generate reactive oxygen species at high rates in both the forward and reverse reactions, J. Biol. Chem. 287 (2012) 27255-27264. source
• Not checked yetcites [100] 100. M.P. Paranagama, K. Sakamoto, H. Amino, M. Awano, H. Miyoshi, K. Kita, Contri- bution of the FAD and quinone binding sites to the production of reactive oxy- gen species from Ascaris suum mitochondrial complex II, Mitochondrion 10 (2010) 158-165. source

In the paper

“The activity of complex II is directly influenced by the concentration of other TCA cycle metabolites, since malate, fumarate, citrate and especially oxaloacetate [65][66][67] have been shown to inhibit competitively with succinate.”

What the sources say

• Not checked yetcites [65][66][67]

In the paper

“Furthermore, this ROS production was completely sensitive to the competitive carboxylate site inhibitor malonate and was only partially repressed by the Q-site inhibitor atpenin A5.Therefore, the authors concluded that the ROS must have been produced at the flavin site of complex II [37].”

What the sources say

• Not checked yetcites [37] 37. C.L. Quinlan, A.L. Orr, I.V. Perevoshchikova, J.R. Treberg, B.A. Ackrell, M.D. Brand, Mitochondrial complex II can generate reactive oxygen species at high rates in both the forward and reverse reactions, J. Biol. Chem. 287 (2012) 27255-27264. source

In the paper

“Messner and Imlay concluded that QFR releases superoxide from the fully reduced flavin if the [2Fe-2S] cluster is available to sequester the semiquinone electron; otherwise this electron is rapidly transferred to the nascent superoxide and hydrogen peroxide is released [101].”

What the sources say

• Not checked yetcites [101] 101. K.R. Messner, J.A. Imlay, Mechanism of superoxide and hydrogen peroxide for- mation by fumarate reductase, succinate dehydrogenase, and aspartate oxidase, J. Biol. Chem. 277 (2002) 42563-42571. source

In the paper

“An ambivalence of mitochondrial ROS production has been also detected in the context of ischemia/reperfusion and ischemic or pharmacological preconditioning: while reactive oxygen species are among the main determinants of cellular damage during longer periods of ischemia and reperfusion, there is also ample evidence that mitochondrial ROS production is involved in cardioprotective signaling”

What the sources say

• Not checked yetcites [8,[38][39][40]

In the paper

“The protective effects of complex II inhibitors could then be explained by their differential effects on complex I and complex III related ROS production: they reduce ROS that are generated at complex I by reverse electron transfer (RET) during reperfusion while they promote production of ROS at the Q o site of complex III by shifting the redox state of the Q-pool to an intermediate state [15].”

What the sources say

• Not checked yetcites [15] 15. S. Dröse, P.J. Hanley, U. Brandt, Ambivalent effects of diazoxide on mitochondrial ROS production at respiratory chain complexes I and III, Biochim. Biophys. Acta 1790 (2009) 558-565. source

In the paper

“In coupled mitochondria and SMP, high ROS production is observed under these conditions, but this can be largely attributed to complex I due to reverse electron transfer from complex II, since (i) it is sensitive to complex I inhibitors like rotenone [18][19][20]24,91,92], (ii) requires a high membrane potential, i.e. is sensitive to uncouplers and ionophores [15,[18][19][20]91] or ADP (that”

What the sources say

• Not checked yetcites [18][19][20]24,91,92]
• Not checked yetcites [15,[18][19][20]91]
• Not checked yetcites [32] 32. S. Dröse, U. Brandt, The mechanism of mitochondrial superoxide production by the cytochrome bc 1 complex, J. Biol. Chem. 283 (2008) 21649-21654. source
• Not checked yetcites [93] 93. Q. Chen, E.J. Vazquez, S. Moghaddas, C.L. Hoppel, E.J. Lesnefsky, Production of re- active oxygen species by mitochondria: central role of complex III, J. Biol. Chem. 278 (2003) 36027-36031. source

In the paper

“The succinate-dependent ROS generation of SMP from adult worms, that do not contain complex III and IV activities in their respiratory chain, was not influenced by a complex I inhibitor and was completely and partially suppressed by malonate or atpenin A5, respectively.This indicates that complex II is the exclusive ROS source under these conditions.”

What the sources say

• Not checked yetcites [100] 100. M.P. Paranagama, K. Sakamoto, H. Amino, M. Awano, H. Miyoshi, K. Kita, Contri- bution of the FAD and quinone binding sites to the production of reactive oxy- gen species from Ascaris suum mitochondrial complex II, Mitochondrion 10 (2010) 158-165. source

In the paper

“This was also confirmed by Quinlan et al. [37], however these authors also observed that complex II in isolated rat skeletal mitochondria produced ROS at a significant rate with succinate concentrations below 5 mM (with a peak at around 400 μM) and when the downstream respiratory chain was inhibited.”

What the sources say

• Not checked yetcites [37] 37. C.L. Quinlan, A.L. Orr, I.V. Perevoshchikova, J.R. Treberg, B.A. Ackrell, M.D. Brand, Mitochondrial complex II can generate reactive oxygen species at high rates in both the forward and reverse reactions, J. Biol. Chem. 287 (2012) 27255-27264. source

In the paper

“Finally, it was shown that the complex II related rates approach or exceed the maximum rates of complexes I and III indicating that complex II may be an important contributor to physiological and pathological ROS production [37].”

What the sources say

• Not checked yetcites [37] 37. C.L. Quinlan, A.L. Orr, I.V. Perevoshchikova, J.R. Treberg, B.A. Ackrell, M.D. Brand, Mitochondrial complex II can generate reactive oxygen species at high rates in both the forward and reverse reactions, J. Biol. Chem. 287 (2012) 27255-27264. source

In the paper

“Both enzymes produced ROS with a linear dependence on the dissolved oxygen concentration, although SQR produced ROS at a much lower rate.”

What the sources say

• Not checked yetcites [101] 101. K.R. Messner, J.A. Imlay, Mechanism of superoxide and hydrogen peroxide for- mation by fumarate reductase, succinate dehydrogenase, and aspartate oxidase, J. Biol. Chem. 277 (2002) 42563-42571. source

In the paper

“Besides a direct competition between succinate and malate, it has been observed that complex II can oxidize malate to the enol form oxaloacetate [67,68], which binds to the dicarboxylate binding site with high affinity [66].”

What the sources say

• Not checked yetcites [67] 67. B.A.C. Ackrell, E.B. Kearney, M. Mayr, Studies on succinate-dehydrogenase. 24. Role of oxalacetate in regulation of mammalian succinate-dehydrogenase, J. Biol. Chem. 249 (1974) 2021-2027. source
• Not checked yetcites [68] 68. Y.O. Belikova, A.B. Kotlyar, A.D. Vinogradov, Oxidation of malate by the mitochon- drial succinate-ubiquinone reductase, Biochim. Biophys. Acta 936 (1988) 1-9. source
• Not checked yetcites [66] 66. E.B. Kearney, B.A.C. Ackrell, M. Mayr, Tightly bound oxalacetate and activation of succinated dehydrogenase, Biochem. Biophys. Res. Commun. 49 (1972) 1115-1121. source

In the paper

“The succinate concentration in different tissues and mitochondria is in the submillimolar range under aerobic conditions [22,72,73], indicating that complex II is not working at maximal velocity under 'standard conditions'.”

What the sources say

• Not checked yetcites [22] 22. A.A. Starkov, The role of mitochondria in reactive oxygen species metabolism and signaling, Ann. N. Y. Acad. Sci. 1147 (2008) 37-52. source
• Not checked yetcites [72] 72. S. Hoyer, C. Krier, Ischemia and the aging brain -studies on glucose and energy-metabolism in rat cerebral-cortex, Neurobiol. Aging 7 (1986) 23-29. source
• Not checked yetcites [73] 73. K. Brockmann, A. Bjornstad, P. Dechent, C.G. Korenke, J. Smeitink, J.M.F. Trijbels, S. Athanassopoulos, R. Villagran, O.H. Skjeldal, E. Wilichowski, J. Frahm, F. Hanefeld, Succinate in dystrophic white matter: a proton magnetic resonance spectroscopy finding characteristic for complex II deficiency, Ann. Neurol. 52 (2002) 38-46. source

In the paper

“This can be explained by an increased oxidation of the Q-pool, since it was shown that the superoxide generation at the Q o site is maximal at intermediate reduction states of the ubiquinone pool if the Q i site is blocked by antimycin A [25,32,33].”

What the sources say

• Not checked yetcites [25] 25. L. Bleier, S. Dröse, Superoxide generation by complex III: from mechanistic rationales to functional consequences, Biochim. Biophys, Acta (2013), http://dx.doi.org/10. 1016/j.bbabio.2012.12.002. source
• Not checked yetcites [32] 32. S. Dröse, U. Brandt, The mechanism of mitochondrial superoxide production by the cytochrome bc 1 complex, J. Biol. Chem. 283 (2008) 21649-21654. source
• Not checked yetcites [33] 33. C.L. Quinlan, A.A. Gerencser, J.R. Treberg, M.D. Brand, The mechanism of super- oxide production by the antimycin-inhibited mitochondrial Q-cycle, J. Biol. Chem. 286 (2011) 31361-31372. source

In the paper

“In SQR the high potential centers ([3Fe-4S] and heme b, which attract electrons and pull them away from the dicarboxylate site) are close to the Q site, while in QFR, FAD and the [2Fe-2S] clusters have the highest redox potentials and hence accumulate electrons close to the dicarboxylate binding site.”

What the sources say

• Not checked yetcites [12] 12. V. Yankovskaya, R. Horsefield, S. Tornroth, C. Luna-Chavez, C. Leger, B. Byrne, G. Cecchini, S. Iwata, Architecture of succinate dehydrogenase and reactive oxygen species generation, Science 299 (2003) 700-704. source

In the paper

“it was suggested by Muller et al. that the differential contribution of TCA cycle enzymes and the conditional removal of the endogenous complex II inhibitor oxaloacetate are key factors that control succinate-dependent ROS generation [23].”

What the sources say

• Not checked yetcites [23] 23. F.L. Muller, Y.H. Liu, M.A. Abdul-Ghani, M.S. Lustgarten, A. Bhattacharya, Y.C. Jang, H. Van Remmen, High rates of superoxide production in skeletal-muscle mitochondria respiring on both complex I-and complex II-linked substrates, Biochem. J. 409 (2008) 491-499. source

In the paper

“Zoccarato and colleagues have shown that under these conditions electrons can flow downstream through complex I, which should attenuate RET [21].”

What the sources say

• Not checked yetcites [21] 21. F. Zoccarato, L. Cavallini, S. Bortolami, A. Alexandre, Succinate modulation of H 2 O 2 release at NADH:ubiquinone oxidoreductase (complex I) in brain mito- chondria, Biochem. J. 406 (2007) 125-129. source

In the paper

“They have proposed that the reduction of the succinate-dependent ROS formation by malate is due to an accumulation of oxaloacetate that occurs unless acetyl-CoA is available.”

What the sources say

• Not checked yetcites [23] 23. F.L. Muller, Y.H. Liu, M.A. Abdul-Ghani, M.S. Lustgarten, A. Bhattacharya, Y.C. Jang, H. Van Remmen, High rates of superoxide production in skeletal-muscle mitochondria respiring on both complex I-and complex II-linked substrates, Biochem. J. 409 (2008) 491-499. source

In the paper

“other studies demonstrated that different NADH-generating substrates have an opposing effect on ROS generation [23,35,108]”

What the sources say

• Not checked yetcites [23] 23. F.L. Muller, Y.H. Liu, M.A. Abdul-Ghani, M.S. Lustgarten, A. Bhattacharya, Y.C. Jang, H. Van Remmen, High rates of superoxide production in skeletal-muscle mitochondria respiring on both complex I-and complex II-linked substrates, Biochem. J. 409 (2008) 491-499. source
• Not checked yetcites [35] 35. F. Zoccarato, C. Miotto, L. Cavallini, A. Alexandre, The control of mitochon- drial succinate-dependent H 2 O 2 production, J. Bioenerg. Biomembr. 43 (2011) 359-366. source
• Not checked yetcites [108] 108. S. Bortolami, E. Comelato, F. Zoccarato, A. Alexandre, L. Cavallini, Long chain fatty acyl-CoA modulation of H 2 O 2 release at mitochondrial complex I, J. Bioenerg. Biomembr. 40 (2008) 9-18. source

In the paper

“In principle, fully reduced FAD can either transfer one electron onto molecular oxygen which leads to the formation of superoxide (probably the major reaction in complex II, but only confirmed for E. coli SQR [101]) or it may also transfer both electrons onto O 2 which leads to the formation of H 2 O 2 (as shown for E. coli QFR [101]) (Fig. 2B).”

What the sources say

• Not checked yetcites [101] 101. K.R. Messner, J.A. Imlay, Mechanism of superoxide and hydrogen peroxide for- mation by fumarate reductase, succinate dehydrogenase, and aspartate oxidase, J. Biol. Chem. 277 (2002) 42563-42571. source

In the paper

“Mutants of E. coli SQR that do not contain heme b showed an unchanged ROS generation, indicating that this prosthetic group is not serving as a 'sink' for excess electrons [102,103].”

What the sources say

• Not checked yetcites [102] 102. Q.M. Tran, R.A. Rothery, E. Maklashina, G. Cecchini, J.H. Weiner, Escherichia coli suc- cinate dehydrogenase variant lacking the heme b, Proc. Natl. Acad. Sci. U. S. A. 104 (2007) 18007-18012. source
• Not checked yetcites [103] 103. Q.M. Tran, C. Fong, R.A. Rothery, E. Maklashina, G. Cecchini, J.H. Weiner, Out of plane distortions of the heme b of Escherichia coli succinate dehydrogenase, PLoS One 7 (2012). source

In the paper

“Yankovskaya et al. [12] proposed that the key difference in the ROS production by E. coli SQR and QFR lies in the differential arrangement of redox potentials among the redox centers.”

What the sources say

• Not checked yetcites [12] 12. V. Yankovskaya, R. Horsefield, S. Tornroth, C. Luna-Chavez, C. Leger, B. Byrne, G. Cecchini, S. Iwata, Architecture of succinate dehydrogenase and reactive oxygen species generation, Science 299 (2003) 700-704. source

In the paper

“While alternative explanations for the source or mechanism of ROS production under these conditions have been proposed [34,36], the prevalent view is that under these conditions ROS are produced by complex I due to RET from complex II [18][19][20]23].”

What the sources say

• Not checked yetcites [34] 34. F. Zoccarato, L. Cavallini, A. Alexandre, Succinate is the controller of O 2 -•/H 2 O 2 release at mitochondrial complex I: negative modulation by malate, positive by cyanide, J. Bioenerg. Biomembr. 41 (2009) 387-393. source
• Not checked yetcites [36] 36. S.J. Ralph, R. Moreno-Sanchez, J. Neuzil, S. Rodriguez-Enriquez, Inhibitors of suc- cinate: quinone reductase/complex II regulate production of mitochondrial re- active oxygen species and protect normal cells from ischemic damage but induce specific cancer cell death, Pharm. Res. 28 (2011) 2695-2730. source
• Not checked yetcites [18][19][20]23]

In the paper

“While these arrangements favor the respective physiological activity (i.e., ubiquinone reduction for SQR and fumarate reduction/menaquinol oxidation for QFR) they also presuppose a differential disposition for superoxide production under aerobic conditions.”

What the sources say

• Not checked yetcites [12] 12. V. Yankovskaya, R. Horsefield, S. Tornroth, C. Luna-Chavez, C. Leger, B. Byrne, G. Cecchini, S. Iwata, Architecture of succinate dehydrogenase and reactive oxygen species generation, Science 299 (2003) 700-704. source

In the paper

“While a contribution of the Q site might occur in the respective mutants, the most likely source of ROS in wild-type complex II is the fully reduced FAD [37,101].”

What the sources say

• Not checked yetcites [37] 37. C.L. Quinlan, A.L. Orr, I.V. Perevoshchikova, J.R. Treberg, B.A. Ackrell, M.D. Brand, Mitochondrial complex II can generate reactive oxygen species at high rates in both the forward and reverse reactions, J. Biol. Chem. 287 (2012) 27255-27264. source
• Not checked yetcites [101] 101. K.R. Messner, J.A. Imlay, Mechanism of superoxide and hydrogen peroxide for- mation by fumarate reductase, succinate dehydrogenase, and aspartate oxidase, J. Biol. Chem. 277 (2002) 42563-42571. source

In the paper

“However, atpenin A5 induced ROS generation by complex II was somewhat lower than ROS generation induced by a further downstream block (at the complex III Q o site by myxothialzol), which has been explained by an alteration of the succinate dehydrogenase activity upon atpenin A5 binding [37].”

What the sources say

• Not checked yetcites [37] 37. C.L. Quinlan, A.L. Orr, I.V. Perevoshchikova, J.R. Treberg, B.A. Ackrell, M.D. Brand, Mitochondrial complex II can generate reactive oxygen species at high rates in both the forward and reverse reactions, J. Biol. Chem. 287 (2012) 27255-27264. source

In the paper

“Recent investigations indicate that mitochondria are not only an important source of ROS, but can also scavenge large quantities of internally and externally produced reactive oxygen species, especially hydrogen peroxide [22,[111][112][113][114][115][116].”

What the sources say

• Not checked yetcites [22,[111][112][113][114][115][116]

In the paper

“Accordingly, inhibition of complex II and attenuation of the succinate supported ROS generation have been shown by Dzeja et al. [130].”

What the sources say

• Not checked yetcites [130] 130. P.P. Dzeja, P. Bast, C. Ozcan, A. Valverde, E.L. Holmuhamedov, D.G.L. Van Wylen, A. Terzic, Targeting nucleotide-requiring enzymes: implications for diazoxide-induced cardioprotection, Am. J. Physiol. 284 (2003) H1048-H1056.

In the paper

“Alternatively, the substrate flow through the TCA cycle differs depending on the substrates, which might affect the activity of the other two mitochondrial NADPH-regenerating enzymes the NADP + -dependent isocitrate dehydrogenase [119,120] and the malic enzyme [118,121].”

What the sources say

• Not checked yetcites [119] 119. L.A. Sazanov, J.B. Jackson, Proton-translocating transhydrogenase and NAD- linked and NADP-linked isocitrate dehydrogenases operate in a substrate cycle which contributes to fine regulation of the tricarboxylic-acid cycle activity in mitochondria, FEBS Lett. 344 (1994) 109-116. source
• Not checked yetcites [120] 120. S.H. Jo, M.K. Son, H.J. Koh, S.M. Lee, I.H. Song, Y.O. Kim, Y.S. Lee, K.S. Jeong, W.B. Kim, J.W. Park, B.J. Song, T.L. Huh, Control of mitochondrial redox balance and cellular defense against oxidative damage by mitochondrial NADP + -dependent isocitrate dehydrogenase, J. Biol. Chem. 276 (2001) 26732. source
• Not checked yetcites [118] 118. J. Rydström, Mitochondrial NADPH, transhydrogenase and disease, Biochim. Biophys. Acta 1757 (2006) 721-726. source
• Not checked yetcites [121] 121. W.H. Ying, NAD + /NADH and NADP + /NADPH in cellular functions and cell death: regulation and biological consequences, Antioxid. Redox Signal. 10 (2008) 179-206. source

In the paper

“They identified uncouplers and complex I inhibitors as compounds that attenuate the ROS-induced damage in I/R-hearts.”

What the sources say

• Not checked yetcites [123] 123. Q. Chen, A.K.S. Camara, D.F. Stowe, C.L. Hoppel, E.J. Lesnefsky, Modulation of electron transport protects cardiac mitochondria and decreases myocardial in- jury during ischemia and reperfusion, Am. J. Physiol. 292 (2007) C137-C147. source

In the paper

“Hence, the overall ROS release from isolated mitochondria might appear almost unchanged, yet the ROS production is shifted from complex I to complex III.”

In the paper

“Ischemic preconditioning can be mimicked by the K ATP channel opener diazoxide and various other substances, a phenomenon termed pharmacological preconditioning [39].”

What the sources say

• Not checked yetcites [39] 39. P.J. Hanley, J. Daut, K ATP channels and preconditioning: a re-examination of the role of mitochondrial K ATP channels and an overview of alternative mechanisms, J. Mol. Cell. Cardiol. 39 (2005) 17-50. source

In the paper

“The highly effective mitochondrial antioxidative defense system encompasses the thioredoxin/peroxiredoxin system as well as the glutathione/glutathione peroxidase system (overview in [22,117]).”

What the sources say

• Not checked yetcites [22] 22. A.A. Starkov, The role of mitochondria in reactive oxygen species metabolism and signaling, Ann. N. Y. Acad. Sci. 1147 (2008) 37-52. source
• Not checked yetcites [117] 117. C.C. Winterbourn, M.B. Hampton, Thiol chemistry and specificity in redox sig- naling, Free Radic. Biol. Med. 45 (2008) 549-561. source

In the paper

“Diazoxide transiently induces increased ROS production [43,[131][132][133], which is in agreement with the view that mitochondria-derived reactive oxygen species are involved in cardioprotective signaling during ischemic and pharmacological preconditioning (overview in [8,39,40]).”

What the sources say

• Not checked yetcites [43,[131][132][133]
• Not checked yetcites [8] 8. A.P. Halestrap, S.J. Clarke, I. Khaliulin, The role of mitochondria in protection of the heart by preconditioning, Biochim. Biophys. Acta 1767 (2007) 1007-1031. source
• Not checked yetcites [39] 39. P.J. Hanley, J. Daut, K ATP channels and preconditioning: a re-examination of the role of mitochondrial K ATP channels and an overview of alternative mechanisms, J. Mol. Cell. Cardiol. 39 (2005) 17-50. source
• Not checked yetcites [40] 40. L.S. Burwell, S.M. Nadtochiy, P.S. Brookes, Cardioprotection by metabolic shut-down and gradual wake-up, J. Mol. Cell. Cardiol. 46 (2009) 804-810. source

In the paper

“It has been recognized that the mitochondria are both targets and sources of injury during cardiac ischemia and reperfusion [123].”

What the sources say

• Not checked yetcites [123] 123. Q. Chen, A.K.S. Camara, D.F. Stowe, C.L. Hoppel, E.J. Lesnefsky, Modulation of electron transport protects cardiac mitochondria and decreases myocardial in- jury during ischemia and reperfusion, Am. J. Physiol. 292 (2007) C137-C147. source

In the paper

“ROS production under these conditions is therefore not only attenuated by both classes of complex II inhibitors, but also by uncouplers, ionophores and complex I inhibitors.”

In the paper

“However, the damage occurring during ischemia/reperfusion (I/R) can be reduced by ischemic preconditioning where the prolonged ischemic period is preceded by one or more brief (2-5 min) cycles of ischemia and reperfusion [8,39,124].”

What the sources say

• Not checked yetcites [8] 8. A.P. Halestrap, S.J. Clarke, I. Khaliulin, The role of mitochondria in protection of the heart by preconditioning, Biochim. Biophys. Acta 1767 (2007) 1007-1031. source
• Not checked yetcites [39] 39. P.J. Hanley, J. Daut, K ATP channels and preconditioning: a re-examination of the role of mitochondrial K ATP channels and an overview of alternative mechanisms, J. Mol. Cell. Cardiol. 39 (2005) 17-50. source
• Not checked yetcites [124] 124. D.M. Yellon, J.M. Downey, Preconditioning the myocardium: from cellular phys- iology to clinical cardiology, Phys. Rev. 83 (2003) 1113-1151. source

In the paper

“A high succinate concentration and elevated complex II activity will suppress ROS generation from FAD, but will induce superoxide production at complex I due to RET (Fig. 3A).”

In the paper

“Diazoxide as well as several very brief ischemic intervals (10 s) during the early phase of reperfusion also improve the recovery of the heart and reduce infarct size, a phenomenon termed postconditioning [8].”

What the sources say

• Not checked yetcites [8] 8. A.P. Halestrap, S.J. Clarke, I. Khaliulin, The role of mitochondria in protection of the heart by preconditioning, Biochim. Biophys. Acta 1767 (2007) 1007-1031. source

In the paper

“This site has been considered as a source for mitochondria-derived 'signaling ROS' in several cellular processes including the stabilization of the hypoxia-inducible factor 1-α [135][136][137].”

What the sources say

• Not checked yetcites [135][136][137]

In the paper

“Importantly, diazoxide and ischemic preconditioning associated ROS production is attenuated by myxothiazol [132,134], which clearly indicates that the Q o site of complex III is the source.”

What the sources say

• Not checked yetcites [132] 132. O. Oldenburg, M.V. Cohen, J.M. Downey, Mitochondrial K ATP channels in preconditioning, J. Mol. Cell. Cardiol. 35 (2003) 569-575. source
• Not checked yetcites [134] 134. T.L. Vanden Hoek, L.B. Becker, Z. Shao, C. Li, P.T. Schumacker, Reactive oxygen spe- cies released from mitochondria during brief hypoxia induce preconditioning in cardiomyocytes, J. Biol. Chem. 273 (1998) 18092-18098. source

In the paper

“It seems plausible that both substance groups exert their protective effects by suppressing the RET-induced superoxide production by complex I (Section 3.2), but Chen et al. suggested complex III as the source of ROS [123].”

What the sources say

• Not checked yetcites [123] 123. Q. Chen, A.K.S. Camara, D.F. Stowe, C.L. Hoppel, E.J. Lesnefsky, Modulation of electron transport protects cardiac mitochondria and decreases myocardial in- jury during ischemia and reperfusion, Am. J. Physiol. 292 (2007) C137-C147. source

In the paper

“It is well known that a prolonged period of ischemia followed by reperfusion irreversibly damages the heart and other tissues (overview in [8,9]).”

What the sources say

• Not checked yetcites [8] 8. A.P. Halestrap, S.J. Clarke, I. Khaliulin, The role of mitochondria in protection of the heart by preconditioning, Biochim. Biophys. Acta 1767 (2007) 1007-1031. source
• Not checked yetcites [9] 9. D.M. Yellon, D.J. Hausenloy, Mechanisms of disease: myocardial reperfusion in- jury, N. Engl. J. Med. 357 (2007) 1121-1135. source

In the paper

“During ischemia, only a small increase of ROS has been detected, but a burst occurs upon reperfusion [43,125].”

What the sources say

• Not checked yetcites [43] 43. P. Pasdois, B. Beauvoit, L. Tariosse, B. Vinassa, S. Bonoron-Adele, P. Dos Santos, Effect of diazoxide on flavoprotein oxidation and reactive oxygen species gener- ation during ischemia-reperfusion: a study on Langendorff-perfused rat hearts using optic fibers, Am. J. Physiol. 294 (2008) H2088-H2097.
• Not checked yetcites [125] 125. L.G. Kevin, A.K.S. Camara, M.L. Riess, E. Novalija, D.F. Stowe, Ischemic preconditioning alters real-time measure of O 2 radicals in intact hearts with is- chemia and reperfusion, Am. J. Physiol. 284 (2003) H566-H574.

In the paper

“However, there is general uncertainty whether the applied concentration in various test systems will result in similar effective concentrations, which might be largely influenced by the partition coefficient and relative membrane permeability of the applied drug.”

In the paper

“Alternatively, diazoxide that probably binds to the Qp site of complex II (unpublished results) might directly induce ROS generation at the FAD at relatively low succinate concentrations (Fig. 3C).”

What the sources say

• Not checked yetcites unpublished results

In the paper

“It has been pointed out that the effects of diazoxide on mitochondrial respiration occur at concentrations that are above the concentrations that are usually applied for mitoK ATP opening [151].”

What the sources say

• Not checked yetcites [151] 151. A.J. Kowaltowski, S. Seetharaman, P. Paucek, K.D. Garlid, Bioenergetic conse- quences of opening the ATP-sensitive K + channel of heart mitochondria, Am. J. Physiol. 280 (2001) H649-H657.

In the paper

“Hence, it is uncertain whether this mechanism correctly describes ROS generation in vivo.”

In the paper

“It was concluded from many investigations that diazoxide targets a mitochondrial form of ATP-dependent K + channels (mitoK ATP ) and that this channel plays a central role in cardioprotection by ischemic and pharmacological preconditioning and by ischemic postconditioning [140][141][142].”

What the sources say

• Not checked yetcites [140][141][142]

In the paper

“The effect of atpenin A5 was independent of complex II inhibition, and the authors suggested that opening of the putative mitoK ATP channel is the underlying mechanism.”

What the sources say

• Not checked yetcites [44] 44. A.P. Wojtovich, P.S. Brookes, The complex II inhibitor atpenin A5 protects against cardiac ischemia-reperfusion injury via activation of mitochondrial K-ATP channels, Basic Res. Cardiol. 104 (2009) 121-129. source

In the paper

“Hence, an alternative hypothesis was presented that relates the cardioprotective effects of atpenins to the modulation of mitochondrial ROS production [16].”

What the sources say

• Not checked yetcites [16] 16. S. Dröse, L. Bleier, U. Brandt, A common mechanism links differently acting com- plex II inhibitors to cardioprotection: modulation of mitochondrial reactive ox- ygen species production, Mol. Pharmacol. 79 (2011) 814-822. source

In the paper

“Recently, a model was presented that merges these two conflicting views, i.e. that complex II may be a component or regulator of the mitoK ATP channel [44,156,157].”

What the sources say

• Not checked yetcites [44] 44. A.P. Wojtovich, P.S. Brookes, The complex II inhibitor atpenin A5 protects against cardiac ischemia-reperfusion injury via activation of mitochondrial K-ATP channels, Basic Res. Cardiol. 104 (2009) 121-129. source
• Not checked yetcites [156] 156. H. Ardehali, Z.H. Chen, Y. Ko, R. Mejia-Alvarez, E. Marban, Multiprotein complex containing succinate dehydrogenase confers mitochondrial ATP-sensitive K + channel activity, Proc. Natl. Acad. Sci. U. S. A. 101 (2004) 11880-11885. source
• Not checked yetcites [157] 157. A.P. Wojtovich, P.S. Brookes, The endogenous mitochondrial complex II inhibitor malonate regulates mitochondrial ATP-sensitive potassium channels: implications for ischemic preconditioning, Biochim. Biophys. Acta 1777 (2008) 882-889. source

In the paper

“Especially, the fact that the K ATP channel subunits could not be identified so far in highly purified mitochondria challenges its existence [145,146].”

What the sources say

• Not checked yetcites [145] 145. T. Brustovetsky, N. Shalbuyeva, N. Brustovetsky, Lack of manifestations of diazoxide/5-hydroxydecanoatesensitive K ATP channel in rat brain nonsynaptosomal mitochondria, J. Physiol. Lond. 568 (2005) 47-59. source
• Not checked yetcites [146] 146. D.B. Foster, J.J. Rucker, E. Marban, Is Kir6.1 a subunit of mitoK ATP ? Biochem. Biophys. Res. Commun. 366 (2008) 649-656. source

In the paper

“Diazoxide inhibits complex II [128,129,147], while the K ATP channel antagonist 5-HD can be metabolized by the ß-oxidation pathway of the mitochondria [148][149][150].”

What the sources say

• Not checked yetcites [128] 128. P.J. Hanley, M. Mickel, M. Löffler, U. Brandt, J. Daut, K ATP channel-independent targets of diazoxide and 5-hydroxydecanoate in the heart, J. Physiol. 542 (2002) 735-741. source
• Not checked yetcites [129] 129. S. Dröse, U. Brandt, P.J. Hanley, K + -independent actions of diazoxide question the role of inner membrane K ATP channels in mitochondrial cytoprotective sig- naling, J. Biol. Chem. 281 (2006) 23733-23739. source
• Not checked yetcites [147] 147. S. Ovide-Bordeaux, R. Ventura-Clapier, V. Veksler, Do modulators of the mito- chondrial K ATP channel change the mitochondria in situ? J. Biol. Chem. 275 (2000) 37291-37295. source
• Not checked yetcites [148][149][150]

In the paper

“However, the existence of such a mitoK ATP channel is controversial [8,39,[142][143][144].”

What the sources say

• Not checked yetcites [8,39,[142][143][144]