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Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I
Open accessAbstract
Oxidative damage from elevated production of reactive oxygen species (ROS) contributes to ischemia-reperfusion injury in myocardial infarction and stroke. The mechanism by which the increase in ROS occurs is not known, and it is unclear how this increase can be prevented. A wide variety of nitric oxide donors and S-nitrosating agents protect the ischemic myocardium from infarction, but the responsible mechanisms are unclear. Here we used a mitochondria-selective S-nitrosating agent, MitoSNO, to determine how mitochondrial S-nitrosation at the reperfusion phase of myocardial infarction is cardioprotective in vivo in mice. We found that protection is due to the S-nitrosation of mitochondrial complex I, which is the entry point for electrons from NADH into the respiratory chain. Reversible S-nitrosation of complex I slows the reactivation of mitochondria during the crucial first minutes of the reperfusion of ischemic tissue, thereby decreasing ROS production, oxidative damage and tissue necrosis. Inhibition of complex I is afforded by the selective S-nitrosation of Cys39 on the ND3 subunit, which becomes susceptible to modification only after ischemia. Our results identify rapid complex I reactivation as a central pathological feature of ischemia-reperfusion injury and show that preventing this reactivation by modification of a cysteine switch is a robust cardioprotective mechanism and hence a rational therapeutic strategy.
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“Conversely, S-nitrosation of the other three cysteines was unaffected by changes in complex I activity (Fig. 2d and Supplementary Figs. 8–10).”
§ Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I > Abstract
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“MitoSNO reproducibly S-nitrosated three subunits: the 75 kDa, B8 and ND3 subunits (Fig. 2b,c, Supplementary Fig. 7b and Supplementary Table 2).”
§ Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I > Abstract
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“Notably, MitoSNO treatment did not inhibit complex I in the normoxic myocardium in vivo (Fig. 1g)”
§ Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I > Abstract
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“MitoSNO administered at reperfusion significantly decreased infarct size (Fig. 1b and Supplementary Fig. 2).”
§ Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I > Abstract
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“we identified four cysteines that were S-nitrosated by MitoSNO: two on the 75 kDa subunit and one each on the ND3 and B8 subunits (Fig. 2c,d and Supplementary Table 3).”
§ Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I > Abstract
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“Using this method, we found that only respiratory complex I and the FoF1-ATP synthase were detectably S-nitrosated within mitochondria in vivo (Fig. 1f, Supplementary Fig. 6a and Supplementary Table 1).”
§ Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I > Abstract
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“In the MitoSNO-treated mice, complex I activity returned to its initial levels after 30 min”
§ Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I > Abstract
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“Although S-nitrosation did not affect FoF1-ATP synthase activity (Supplementary Fig. 6b)”
§ Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I > Abstract
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“MitoSNO did not alter hemodynamics (Supplementary Fig. 4).”
§ Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I > Abstract
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“S-nitrosation of ND3 Cys39 was negligible under conditions of high activity but increased markedly under conditions of low activity (Fig. 2d).”
§ Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I > Abstract
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“Neither SNAP nor the MitoSNO-targeting moiety (MitoNAP)11 had this effect (Fig. 1b).”
§ Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I > Abstract
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“In contrast, in the absence of MitoSNO treatment in vivo, complex I was not affected after 5 min of reperfusion, but its activity then decreased by ~50% during 30 min of reperfusion and could not be restored ex vivo by reductants”
§ Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I > Abstract
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“Within the intact, ischemic heart perfused ex vivo in a Langendorff system, there was substantial (~40%) S-nitrosation of ND3 by MitoSNO that was not present in normoxic hearts; in contrast, the amount of S-nitrosation of the 75 kDa subunit cysteines was similar under normoxia and ischemia (Fig. 3a, Supplementary Table 4 and Supplementary Fig. 11).”
§ Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I > Abstract
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“MitoSNO administered at reperfusion blocked this rise in the amount of hydrogen peroxide, whereas administration of SNAP did not (Fig. 1c).”
§ Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I > Abstract
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“This led to the selective S-nitrosation of mitochondrial proteins in the reperfused heart (Fig. 1a), as visualized by labeling with a red fluorescent probe15–17. In contrast, equal doses of the untargeted precursor S-nitrosating compound S-nitroso-N-acetylpenicillamine (SNAP) S-nitrosated only nonmitochondrial myocardial and plasma proteins (Fig. 1a).”
§ Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I > Abstract
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“Intravenous injection of MitoSNO into mice also resulted in S-nitrosation of the ND3 cysteine in vivo during reperfusion of the ischemic heart, whereas MitoSNO injection did not have this effect in normoxic hearts (Fig. 3b).”
§ Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I > Abstract
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“Complex I activity was lower in heart mitochondria from MitoSNO-treated mice compared to untreated mice, and this decreased activity was normalized by selective S-nitrosothiol reduction using copper and ascorbate15–17 (Fig. 1g).”
§ Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I > Abstract
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“Moreover, ND3 Cys39 was extensively S-nitrosated (>50%) by MitoSNO in isolated rat heart mitochondria during anoxia but was negligibly modified under normoxic conditions (Fig. 2e,f).”
§ Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I > Abstract
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“MitoSNO was protective only during reperfusion: injection 10 min after reperfusion was ineffective (Supplementary Fig. 3).”
§ Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I > Abstract
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“Using MitoB we found that the amount of mitochondrial hydrogen peroxide remained low during ischemia and increased only after reperfusion in vivo (Fig. 1c).”
§ Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I > Abstract
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“The rise in the amount of mitochondrial hydrogen peroxide was associated with increased protein carbonylation (Fig. 1d), a marker of oxidative damage, as well as necrotic (Fig. 1b) and apoptotic (Fig. 1e) cell death, and these effects were all prevented by MitoSNO.”
§ Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I > Abstract
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“MitoSNO protected control cardiomyocytes treated with a scrambled RNAi construct from ischemia-reperfusion injury, but decreasing complex I activity by NDUFAF1-targeted RNAi completely abolished MitoSNO protection (Fig. 4a).”
§ Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I > Abstract
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“Copper and ascorbate treatment restored complex I activity, indicating that the inhibition of activity was due to S-nitrosation of ND3 Cys39 (Fig. 3d).”
§ Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I > Abstract
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“Exposure of isolated bovine heart mitochondrial membranes to MitoSNO under conditions in which complex I is in a high activity state led to S-nitrosation of the 75 kDa and B8 subunit cysteines but not of the ND3 subunit, and this exposure did not affect complex I activity (Fig. 3d).”
§ Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I > Abstract
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“We selectively knocked down expression of the complex I assembly factor NDUFAF1 (ref. 36) by RNAi, which decreased protein amounts by 80% (Supplementary Fig. 16a–c) and lowered complex I activity (Supplementary Fig. 16d) while leaving the amount of complex II unaffected (Supplementary Fig. 16a,e).”
§ Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I > Abstract
What the sources say
- Not checked yetcites [36] Mimaki, M. et al. Understanding mitochondrial complex I assembly in health and disease. Biochim. Biophys. Acta 1817, 851–862 (2012). source
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“Our model shows that Cys39 is located at the hinge region of complex I facing the mitochondrial matrix. Furthermore, Cys39 is adjacent to the half-channel element of one of the four proposed proton translocation pathways of complex I and is close to the ubiquinone binding pocket, where ubiquinone receives electrons from the N2 iron-sulfur center (Fig. 3g)34.”
§ Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I > Abstract
What the sources say
- Not checked yetcites [34] Baradaran, R., Berrisford, J.M., Minhas, G.S. & Sazanov, L.A. Crystal structure of the entire respiratory complex I. Nature 494, 443–448 (2013). source
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- Rests on an assumption: The prokaryotic complex I structures used for modeling are sufficiently homologous to mammalian complex I to locate ND3 Cys39 accurately.
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In the paper
“Nitrite infusion during prolonged ischemia resulted in substantial S-nitrosation of this cysteine, which was negligibly modified by nitrite under normoxic conditions (Fig. 4b,c and Supplementary Table 5).”
§ Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I > Abstract
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“In contrast, incubation with MitoSNO under conditions in which complex I is in a low activity state led to S-nitrosation of ND3 Cys39, as well as of the other three cysteines, and inhibited complex I activity (Fig. 3d).”
§ Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I > Abstract
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In the paper
“Together these data indicate that cardioprotection by MitoSNO acts through mitochondrial S-nitrosation, which inhibits mitochondrial hydrogen peroxide production at reperfusion.”
§ Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I > Abstract
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“As complex I was the only S-nitrosation target identified in our proteomic analysis whose activity was affected by this modification, we consider it to constitute a probable node for cardioprotection.”
§ Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I > Abstract
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“MitoSNO has been reported to be protective in mice with cardiomyocyte deficiency of protein kinase G18, indicating that the cardio-protection conferred by MitoSNO is not due to nonmitochondrial pathways that operate through cyclic GMP–protein kinase G signaling3,6”
§ Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I > Abstract
What the sources say
- Not checked yetcites [18] Methner, C., Lukowski, R., Hofman, F., Murphy, M.P. & Krieg, T. Protection through postconditioning or a mitochondria-targeted S-nitrosothiol is unaffected by cardiomyocyte-selective ablation of protein kinase G. Basic Res. Cardiol. 108, 337 (2013). source
- Not checked yetcites [3] Lundberg, J.O., Weitzberg, E. & Gladwin, M.T. The nitrate-nitrite–nitric oxide pathway in physiology and therapeutics. Nat. Rev. Drug Discov. 7, 156–167 (2008). source
- Not checked yetcites [6] Costa, A.D. et al. Protein kinase G transmits the cardioprotective signal from cytosol to mitochondria. Circ. Res. 97, 329–336 (2005). source
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In the paper
“previous work has shown that complex I is inhibited by various nitric oxide donors in vitro and that this inhibition is associated with S-nitrosation2,10,11,21–24.”
§ Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I > Abstract
What the sources say
- Not checked yetcites [2] Shiva, S. et al. Nitrite augments tolerance to ischemia/reperfusion injury via the modulation of mitochondrial electron transfer. J. Exp. Med. 204, 2089–2102 (2007). source
- Not checked yetcites [10] Sun, J., Morgan, M., Shen, R.F., Steenbergen, C. & Murphy, E. Preconditioning results in S-nitrosylation of proteins involved in regulation of mitochondrial energetics and calcium transport. Circ. Res. 101, 1155–1163 (2007). source
- Not checked yetcites [11] Prime, T.A. et al. A mitochondria-targeted S-nitrosothiol modulates respiration, nitrosates thiols, and protects against ischemia-reperfusion injury. Proc. Natl. Acad. Sci. USA 106, 10764–10769 (2009). source
- Not checked yetcites [21] Clementi, E., Brown, G.C., Feelisch, M. & Moncada, S. Persistent inhibition of cell respiration by nitric oxide: crucial role of S-nitrosylation of mitochondrial complex I and protective action of glutathione. Proc. Natl. Acad. Sci. USA 95, 7631–7636 (1998). source
- Not checked yetcites [22] Burwell, L.S., Nadtochiy, S.M., Tompkins, A.J., Young, S. & Brookes, P.S. Direct evidence for S-nitrosation of mitochondrial complex I. Biochem. J. 394, 627–634 (2006). source
- Not checked yetcites [23] Dahm, C.C., Moore, K. & Murphy, M.P. Persistent S-nitrosation of complex I and other mitochondrial membrane proteins by S-nitrosothiols but not nitric oxide or peroxynitrite. J. Biol. Chem. 281, 10056–10065 (2006). source
- Not checked yetcites [24] Galkin, A. & Moncada, S. S-nitrosation of mitochondrial complex I depends on its structural conformation. J. Biol. Chem. 282, 37448–37453 (2007). source
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In the paper
“These data suggest that complex I ND3 Cys39 is the crucial functional S-nitrosation target and that other interactions of MitoSNO with mitochondria do not contribute to protection.”
§ Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I > Abstract
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In the paper
“This mechanism probably contributes to cardioprotection by untargeted nitric oxide donors and alterations to nitric oxide metabolism in general, although nonmitochondrial pathways may also contribute.”
§ Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I > Abstract
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In the paper
“We assessed infarct size after 120 min of reperfusion using triphenyltetrazolium chloride staining and expressed it as a percentage of the risk zone as described recently40.”
§ Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I > ONLINE METHODS > In vivo treatments
What the sources say
- Not checked yetcites [40] Nadtochiy, S.M., Redman, E., Rahman, I. & Brookes, P.S. Lysine deacetylation in ischaemic preconditioning: the role of SIRT1. Cardiovasc. Res. 89, 643–649 (2011). source
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In the paper
“We used an open-chest, in situ mouse (C57BL/6) heart model as recently described41.”
§ Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I > ONLINE METHODS > In vivo treatments
What the sources say
- Not checked yetcites [41] Schmidt, K. et al. Cardioprotective effects of mineralocorticoid receptor antagonists at reperfusion. Eur. Heart J. 31, 1655–1662 (2010). source
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In the paper
“The nitrite (NO2−) anion protects from ischemia-reperfusion injury in vivo1–3,37 and is thought to act as an S-nitrosating agent in the ischemic myocardium2.”
§ Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I > Abstract
What the sources say
- Not checked yetcites [1] Duranski, M.R. et al. Cytoprotective effects of nitrite during in vivo ischemia-reperfusion of the heart and liver. J. Clin. Invest. 115, 1232–1240 (2005). source
- Not checked yetcites [2] Shiva, S. et al. Nitrite augments tolerance to ischemia/reperfusion injury via the modulation of mitochondrial electron transfer. J. Exp. Med. 204, 2089–2102 (2007). source
- Not checked yetcites [3] Lundberg, J.O., Weitzberg, E. & Gladwin, M.T. The nitrate-nitrite–nitric oxide pathway in physiology and therapeutics. Nat. Rev. Drug Discov. 7, 156–167 (2008). source
- Not checked yetcites [37] Shiva, S. & Gladwin, M.T. Nitrite mediates cytoprotection after ischemia/reperfusion by modulating mitochondrial function. Basic Res. Cardiol. 104, 113–119 (2009). source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“As the S-nitrosation of the ND3 subunit only occurs after anaerobic incubation, these findings suggest that MitoSNO decreases ROS production by S-nitrosating the ND3 subunit.”
§ Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I > Abstract
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In the paper
“To assess differences in protein fluorescence using two-dimensional DIGE, we used an experimental design that included biological variance analysis (BVA)12. In each DIGE experiment, we used four biological replicates, where a biological replicate is an independently prepared heart tissue subjected to the CyDye sample preparations described above.”
§ Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I > ONLINE METHODS > SNO-DIGE experimental design
What the sources say
- Not checked yetcites [12] Chouchani, E.T. et al. Identification of S-nitrosated mitochondrial proteins by S-nitrosothiol difference in gel electrophoresis (SNO-DIGE): implications for the regulation of mitochondrial function by reversible S-nitrosation. Biochem. J. 430, 49–59 (2010). source
plainn = 4- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one. The quote only partly states this claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“We scanned all gels at 100- to 200-μm pixel size, and the photomultiplier tube was set to ensure a maximum pixel intensity within the linear acquisition range for the region of the gel being analyzed (most commonly the sub–20 kDa region of gels containing the complex I ND3 subunit) and thereby ensuring that fluorescent signal intensities were in the linear range.”
§ Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I > ONLINE METHODS > Gel imaging and analysis
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In the paper
“All samples were shielded from light throughout the experiment to preserve S-nitrosothiols.”
§ Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I > ONLINE METHODS > Mitochondrial preparations and incubations
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Reperfusion of the ischemic tissue rapidly reactivates complex I and generates hydrogen peroxide, which causes oxidative damage that leads to the cell death underlying ischemia-reperfusion injury.”
§ Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“All animal experiments described here were carried out in accordance with the UK Home Office Guide on the Operation of Animal (Scientific Procedures) Act of 1986 and the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication 85–23, revised 1996). All procedures were approved under the Project License number PPL 80/2393.”
§ Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I > ONLINE METHODS > In vivo treatments
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“As the ND3 subunit is encoded by mitochondrial DNA, its cysteine cannot be replaced genetically, and there are no known natural mutations or polymorphisms in the gene encoding this subunit (MT-ND3)31.”
§ Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I > Abstract
What the sources say
- Not checked yetcites [31] Bridges, H.R., Birrell, J.A. & Hirst, J. The mitochondrial-encoded subunits of respiratory complex I (NADH:ubiquinone oxidoreductase): identifying residues important in mechanism and disease. Biochem. Soc. Trans. 39, 799–806 (2011). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Together these data suggest that ischemia exposes ND3 Cys39 for S-nitrosation and that this modification specifically mediates the reversible inhibition of complex I in vivo.”
§ Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I > Abstract
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“This result indicates that S-nitrosation of ND3 Cys39 does not disrupt complex I function by affecting the interaction of NADH with the flavin mononucleotide site and that the S-nitrosation of other residues in complex I does not affect its activity.”
§ Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I > Abstract
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In the paper
“We incubated mitochondria or mitochondrial membranes from both the in vitro and in vivo treatment groups in 100 mM NEM to quench unreacted thiols.”
- Also stated in: § Differential labeling of respiratory complex I S-nitrosothiols · plain
“Mitochondria from mice treated in vivo with an S-nitrosating agent were isolated as described above in buffer supplemented with 100 mM NEM before differential labeling.”
§ Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I > ONLINE METHODS > Differential labeling of respiratory complex I S-nitrosothiols
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- Also stated in: § Differential labeling of respiratory complex I S-nitrosothiols · plain
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In the paper
“When protein S-nitrosothiols were to be assessed in mitochondria isolated from hearts that had been subjected to in vivo treatments, 100 mM NEM was included in the isolation buffers.”
§ Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I > ONLINE METHODS > Mitochondrial preparations and incubations
plain- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“When S-nitrosating species are present during reperfusion, the exposed ND3 cysteine becomes S-nitrosated, locking complex I in a low activity state and decreasing ROS production during the reperfusion phase.”
§ Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Pelleted samples were washed three times in Chelex 100–treated PBS before resuspension in 100 μl of the same buffer containing 1 mM ascorbate and 10 μM CuSO4”
§ Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I > ONLINE METHODS > Differential labeling of respiratory complex I S-nitrosothiols
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Error bars represent the s.e.m. from at least three replicates unless otherwise stated.”
§ Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I > ONLINE METHODS > Statistical analyses
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“For analysis, we spiked the tissues with deuterated internal standards, extracted the MitoB and its product MitoP from the reaction with hydrogen peroxide and determined the amounts of MitoB and MitoP present in the tissue by liquid chromatography and tandem mass spectrometry as described previously20.”
§ Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I > ONLINE METHODS > Measurement of mitochondrial hydrogen peroxide flux in vivo
What the sources say
- Not checked yetcites [20] Cochemé, H.M. et al. Measurement of H2O2 within living Drosophila during aging using a ratiometric mass spectrometry probe targeted to the mitochondrial matrix. Cell Metab. 13, 340–350 (2011). source
plain- Asserted: passes — The authors put it forward as true.
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What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“MitoSNO stability was assessed before use from its absorbance at 340 nm.”
§ Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I > ONLINE METHODS > Chemical syntheses
plain- Asserted: passes — The authors put it forward as true.
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What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“NO2− and control saline infusions began 15 min before ischemia and continued throughout the ischemic phase so that a constant final concentration of NO2− was maintained in the heart.”
§ Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I > ONLINE METHODS > Ex vivo heart treatment with nitrite
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“We measured mitochondrial hydrogen peroxide in vivo using the MitoB mass spectro-metric probe as described previously20.”
§ Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I > ONLINE METHODS > Measurement of mitochondrial hydrogen peroxide flux in vivo
What the sources say
- Not checked yetcites [20] Cochemé, H.M. et al. Measurement of H2O2 within living Drosophila during aging using a ratiometric mass spectrometry probe targeted to the mitochondrial matrix. Cell Metab. 13, 340–350 (2011). source
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
In the paper
“We treated mouse hearts with nitrite using previously established protocols known to elicit cardioprotection38.”
§ Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I > ONLINE METHODS > Ex vivo heart treatment with nitrite
What the sources say
- Not checked yetcites [38] Webb, A. et al. Reduction of nitrite to nitric oxide during ischemia protects against myocardial ischemia-reperfusion damage. Proc. Natl. Acad. Sci. USA 101, 13683–13688 (2004). source
boosteddirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
In the paper
“In parallel, we determined the citrate synthase activity of each sample46. We then normalized the complex I rate to the citrate synthase rate and expressed it as a percentage of the appropriate control.”
§ Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I > ONLINE METHODS > Measurement of complex I activity
What the sources say
- Not checked yetcites [46] Srere, P.A. Citrate synthase. Methods Enzymol. 13, 3–10 (1969). source
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“When administering NO2− or saline solutions to ischemic hearts, we deoxygenated the solutions during preparation by bubbling with 95% N2 and 5% CO2.”
§ Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I > ONLINE METHODS > Ex vivo heart treatment with nitrite
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“We protected cells from light during hypoxia (2 h) and reperfusion (1.5 h) and measured cell death using a lactate dehydrogenase (LDH) release assay (Cytotoxicity Detection, Roche Applied Science) according to the manufacturer's instructions.”
§ Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I > ONLINE METHODS > In vitro ischemia reperfusion injury to cells
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
The paper relies on this without support.
Before this study, the existence and physiological importance of S-nitrosation of complex I in vivo had not been demonstrated.
“However, to our knowledge, the existence and physiological importance of S-nitrosation of complex I in vivo has not previously been demonstrated.”
The paper relies on this without support.
The conservation of ND3 Cys39 across metazoans implies that this residue has a physiological role.
“Cys39 in ND3 is conserved throughout metazoans, consistent with a physiological role for this residue.”
The paper relies on this without support.
The prokaryotic complex I structures used for modeling are sufficiently homologous to mammalian complex I to locate ND3 Cys39 accurately.
“We modeled the location of ND3 Cys39 using structures of prokaryotic complex I (refs. 32–34). This modeling led to an orthologous mammalian core structure containing ND3 Cys39”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“Mechanistically, this protection is dependent on MitoSNO transnitrosating a critical cysteine in the active site of complex I.”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [170]
In the citing paper
“This S-nitrosation of Cys39 in the ND3 subunit of complex I inhibits its catalytic activity and, hence, attenuates reverse electron transport and ROS production (170).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [170]
In the citing paper
“For example, MitoSNO (FIGURE 14), a mitochondrially targeted S-nitrosothiol, was shown in rodent models to significantly attenuate infarct size after MI (170).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [170]
In the citing paper
“Murphy and coworkers used a mitochondria-selective S-nitrosating agent to demonstrate that nitrosation of Complex I serves a protective role during ischemia/reperfusion by reducing oxidative damage and tissue necrosis [212, 213].”
From Signaling and stress: The redox landscape in NOS2 biology (2015) · cites this paper as [213]
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Diverse Roles of Mitochondria in Immune Responses: Novel Insights Into Immuno-Metabolism
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Mitochondrial Dysfunction and Myocardial Ischemia-Reperfusion: Implications for Novel Therapies
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“against acute ischemia/reperfusion protocols [69, 80].”
MethodGeneration of Reactive Oxygen Species by Mitochondria
Hernansanz‐Agustín, P., & Enrı́quez, J. A. (2021) · Antioxidants · doi:10.3390/antiox10030415 · Cited by 424
Ischemia/Reperfusion Injury Revisited: An Overview of the Latest Pharmacological Strategies
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A Quantitative Tissue-Specific Landscape of Protein Redox Regulation during Aging
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“the ND3 subunit of mitochondrial complex I is known to stabilize the “deactive” conformation of this target and inhibit enzymatic activity (Chouchani et al., 2013; Galkin et al., 2008).”
Self-citationMechanistic insight from the crystal structure of mitochondrial complex I
Zickermann, V., Wirth, C., Nasiri, H. R., Siegmund, K., Schwalbe, H., Hunte, C., & Brandt, U. (2015) · Science · doi:10.1126/science.1259859 · Cited by 413
The Role of Oxidative Stress in Cardiac Disease: From Physiological Response to Injury Factor
D’Oria, R., Schipani, R., Leonardini, A., Natalicchio, A., Perrini, S., Cignarelli, A., Laviola, L., & Giorgino, F. (2020) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2020/5732956 · Cited by 399
“Hence, rapid complex I reactivation has been identified as a central pathological feature of ischemia-reperfusion, and it has been demonstrated that S-nitrosylation of a cysteine of complex I slows the reactivation of mitochondria during the crucial first minutes of the reperfusion [157].”
BackgroundMetabolic Effects of Dietary Nitrate in Health and Disease
Lundberg, J. O., Carlström, M., & Weitzberg, E. (2018) · Cell Metabolism · doi:10.1016/j.cmet.2018.06.007 · Cited by 374
Mitochondrial VDAC1: A Key Gatekeeper as Potential Therapeutic Target
Camara, A. K. S., Zhou, Y., Wen, P., Tajkhorshid, E., & Kwok, W.-M. (2017) · Frontiers in Physiology · doi:10.3389/fphys.2017.00460 · Cited by 378
“Furthermore, a recent study showed that the modulation of complex I activity by S-nitrosation is cardioprotective against IR injury (Chouchani et al., 2013).”
BackgroundCirculating Nitrite Contributes to Cardioprotection by Remote Ischemic Preconditioning
Rassaf, T., Totzeck, M., Hendgen-Cotta, U. B., Shiva, S., Heusch, G., & Kelm, M. (2014) · Circulation Research · doi:10.1161/circresaha.114.303822 · Cited by 342
“function by S-nitrosation, recently emerging as a key event for cardioprotection.(29,31,49,50) A potential effect on I/R-induced mitochondrial damage or turnover would also be an important aspect, and future studies are needed.”
BackgroundMitochondria in acute myocardial infarction and cardioprotection
Ramachandra, C. J. A., Hernández‐Reséndiz, S., Crespo-Avilan, G. E., Lin, Y., & Hausenloy, D. J. (2020) · EBioMedicine · doi:10.1016/j.ebiom.2020.102884 · Cited by 348
“[12] have also shown that mitochondria-”
Control of mitochondrial superoxide production by reverse electron transport at complex I
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“However, there is now considerable evidence that RET at complex I is a physiological process that underlies mitochondrial redox signaling in a range of situations (11, 13) while also leading to pathological oxidative damage during ischemia–reperfusion injury (1, 14, 15).”
BackgroundSelf-citationThe Role of Oxidative Stress in Myocardial Ischemia and Reperfusion Injury and Remodeling: Revisited
Kurian, G. A., Rajagopal, R., Vedantham, S., & Rajesh, M. (2016) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2016/1656450 · Cited by 343
“Similarly, another study reported that reversible S-nitrosylation of complex I slows the reactivation of mitochondria during the early phase of the reperfusion, thereby reducing ROS production and limiting oxidative tissue damage [50].”
BackgroundStructure and function of mitochondrial complex I
Wirth, C., Brandt, U., Hunte, C., & Zickermann, V. (2016) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2016.02.013 · Cited by 346
“form has been shown to attenuate myocardial ischemia/reperfusion injury in mice by preventing ROS formation by complex I [7].”
BackgroundMitochondrial complex I ROS production and redox signaling in hypoxia
Okoye, C. N., Koren, S. A., & Wojtovich, A. P. (2023) · Redox Biology · doi:10.1016/j.redox.2023.102926 · Cited by 342
“ND3 Cys39 is a critical residue, which when exposed in the D-form is readily modified by ROS resulting in inhibition of complex I activity [138,142,162].”
BackgroundMitochondrial reactive oxygen species production and elimination
Nickel, A. G., Kohlhaas, M., & Maack, C. (2014) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2014.03.011 · Cited by 334
Redox regulation of mitochondrial function with emphasis on cysteine oxidation reactions
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“S-nitrosylation of Cys(39) on the NADH-ubiquinone oxidoreductase chain 3 (ND3) subunit of Complex I occurs only after ischemia [108].”
BackgroundMechanisms of mitochondrial respiratory adaptation
Bennett, C. F., Latorre‐Muro, P., & Puigserver, P. (2022) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-022-00506-6 · Cited by 322
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“A growing body of evidence suggests a central role for the Cys39 residue found within the ND3 subunit of Complex I, and indeed it has recently been demonstrated using the mitochondria-targeted S-nitrosothiol MitoSNO that S-nitrosation of this residue can inhibit the active/deactive transition and so allow dissipation…”
BackgroundSelf-citationMolecular Strategies for Targeting Antioxidants to Mitochondria: Therapeutic Implications
Apostolova, N., & Víctor, V. M. (2014) · Antioxidants and Redox Signaling · doi:10.1089/ars.2014.5952 · Cited by 311
“MitoSNO has been shown to provide protection in an in vivo rodent model of ischemia reperfusion, in which it reversed S-nitrosation of complex I by slowing down the reactivation of mitochondria during the crucial first minutes of reperfusion of ischemic tissue, thereby decreasing ROS production, oxidative damage, and…”
Mitochondrial complex ii: At the crossroads
Bezawork-Geleta, A., Rohlena, J., Dong, L., Pacak, K., & Neuzil, J. (2017) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2017.01.003 · Cited by 295
Role of Oxidative Stress in Reperfusion following Myocardial Ischemia and Its Treatments
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“Based on the report that rapid reactivation of complex I, which generatesH2O2 causing oxidative damage and the cell death, is a core pathological mechanism of MI/RI [170], mitochondria-targeted S-nitrosothiol, a mitochondriaselective S-nitrosating agent, can reversibly S-nitrosify complex I to slow the reactivation of…”
BackgroundMailloux, R. J. (2015) · Redox Biology · doi:10.1016/j.redox.2015.02.001 · Cited by 292
Oxidative Stress and the Use of Antioxidants in Stroke
Shirley, R. B., Ord, E., & Work, L. M. (2014) · Antioxidants · doi:10.3390/antiox3030472 · Cited by 295
“from NADH in the MRC, following ischaemic injury [19,20].”
BackgroundBailey, J. D., Diotallevi, M., NICOL, T., McNeill, E., Shaw, A., Chuaiphichai, S., Hale, A., Starr, A., Nandi, M., Stylianou, E., et al. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.06.018 · Cited by 266
“NO is known to modulate ETC activity through nitrosation of Complex I and competitive inhibition of O 2 -consuming Complex IV (Chouchani et al., 2013; Cleeter et al., 1994) and is responsible for inhibiting oxidative phosphorylation in both activated macrophages and dendritic cells (Everts et al.,…”
Mitochondria as a therapeutic target for ischemic stroke
He, Z., Ning, N., Zhou, Q., Khoshnam, S. E., & Farzaneh, M. (2019) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2019.11.005 · Cited by 272
Mitochondrial Quality Control as a Therapeutic Target
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“I/R and is a potential therapeutic target for the prevention of injury after myocardial and possibly cerebral infarction (Chouchani et al., 2013).”
BackgroundNitric Oxide in Macrophage Immunometabolism: Hiding in Plain Sight
Palmieri, E. M., McGinity, C., Wink, D. A., & McVicar, D. W. (2020) · Metabolites · doi:10.3390/metabo10110429 · Cited by 237
“Considering the history of NO chemistry and the elegant dissection of metabolic mechanisms associated with macrophage cytotoxicity noted above, it is surprising that most in the immunometabolism field have been speculating that the inhibitory effects of NO on oxidative mitochondrial metabolism might be simply due to d…”
BackgroundMitochondrial Respiratory Chain Complexes
Sousa, J. S., D’Imprima, E., & Vonck, J. (2018) · Sub-cellular biochemistry/Subcellular biochemistry · doi:10.1007/978-981-10-7757-9_7 · Cited by 263
Cardiac metabolism as a driver and therapeutic target of myocardial infarction
Zuurbier, C. J., Bertrand, L., Beauloye, C., Andreadou, I., Ruiz‐Meana, M., Jespersen, N. R., Kula‐Alwar, D., Prag, H. A., Bøtker, H. E., Dambrova, M., et al. (2020) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.15180 · Cited by 247
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Cryo-EM structures of complex I from mouse heart mitochondria in two biochemically defined states
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“In addition, S-nitrosation of mitochondrial complex I at specific sites could slow the reactivation and limit ROS production upon reperfusion [38].”
BackgroundHeme Oxygenase-1 and Carbon Monoxide in the Heart
Otterbein, L. E., Foresti, R., & Motterlini, R. (2016) · Circulation Research · doi:10.1161/circresaha.116.306588 · Cited by 217
“The explanation for hypoxia-induced HO-1 could be related to effects on cellular bioenergetics involving mitochondria, where complex I is in a low activity state during cardiac ischemia and is reactivated by reperfusion, generating superoxide and hydrogen peroxide, which cause cell damage and death.(62) HO-1 induction…”
BackgroundMitochondrial Reactive Oxygen Species at the Heart of the Matter
Kornfeld, O. S., Hwang, S., Disatnik, M., Chen, C., Qvit, N., & Mochly‐Rosen, D. (2015) · Circulation Research · doi:10.1161/circresaha.116.305432 · Cited by 215
“MitoSNO reduces infarct size in mice exposed to IR damage.(105) Therefore, targeting PKCε’s mitochondrial substrates to mimic ROS-induced preconditioning may serve as an effec-”
BackgroundAndreadou, I., Iliodromitis, E. K., Rassaf, T., Schulz, R., Papapetropoulos, A., & Ferdinandy, P. (2014) · British Journal of Pharmacology · doi:10.1111/bph.12811 · Cited by 213
“Moreover, a mitochondria-selective S-nitrosating agent, MitoSNO, has been shown to reduce the infarct size in mice (Chouchani et al., 2013).”
BackgroundSIRT3 deficiency exacerbates ischemia-reperfusion injury: implication for aged hearts
Porter, G. A., Urciuoli, W. R., Brookes, P. S., & Nadtochiy, S. M. (2014) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00027.2014 · Cited by 221
Self-citationSuppressors of superoxide production from mitochondrial complex III
Orr, A. L., Vargas, L., Turk, C. N., Baaten, J., Matzen, J., Dardov, V. J., Attle, S. J., Li, J., Quackenbush, D., Goncalves, R. L. S., et al. (2015) · Nature Chemical Biology · doi:10.1038/nchembio.1910 · Cited by 207
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Redox Control of Skeletal Muscle Regeneration
Moal, E. L., Pialoux, V., Juban, G., Groussard, C., Zouhal, H., Chazaud, B., & Mounier, R. (2016) · Antioxidants and Redox Signaling · doi:10.1089/ars.2016.6782 · Cited by 206
“The design of a specific mitochondria-selective S -nitrosating agent, MitoSNO, has been found to be cardioprotective in vivo in mice after ischemia/reperfusion, through the S -nitrosation of mitochondrial complex I, which is the entry point for electrons from NADH into the respiratory chain (62).”
Król, M., & Kepinska, M. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms22010056 · Cited by 187
Therapeutic effects of inorganic nitrate and nitrite in cardiovascular and metabolic diseases
Omar, S. A., Webb, A. J., Lundberg, J. O., & Weitzberg, E. (2016) · Journal of Internal Medicine · doi:10.1111/joim.12441 · Cited by 175
Tian, H., Qian, M., Zhang, Y., Liu, Q., Midgley, A. C., Liu, Y., Che, Y., Hou, J., & Zhao, Q. (2022) · Advanced Science · doi:10.1002/advs.202105408 · Cited by 175
Positive oxidative stress in aging and aging-related disease tolerance
Yan, L. (2014) · Redox Biology · doi:10.1016/j.redox.2014.01.002 · Cited by 176
Understanding and preventing mitochondrial oxidative damage
Murphy, M. P. (2016) · Biochemical Society Transactions · doi:10.1042/bst20160108 · Cited by 165
Self-citationFerdinandy, P., Andreadou, I., Baxter, G. F., Bøtker, H. E., Davidson, S. M., Dobrev, D., Gersh, B. J., Heusch, G., Lecour, S., Ruiz‐Meana, M., et al. (2022) · Pharmacological Reviews · doi:10.1124/pharmrev.121.000348 · Cited by 170
The role of succinate and ROS in reperfusion injury – A critical appraisal
Andrienko, T., Pasdois, P., Pereira, G. C., Ovens, M. J., & Halestrap, A. P. (2017) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2017.06.016 · Cited by 164
Nitrite and nitrate chemical biology and signalling
DeMartino, A. W., Kim‐Shapiro, D. B., Patel, R. P., & Gladwin, M. T. (2018) · British Journal of Pharmacology · doi:10.1111/bph.14484 · Cited by 162
“This action is cytoprotective, as nitrosation of these critical thiols occurs during I/R injury resulting in inhibition of complex I activity, preventing generation of damaging ROS as well as cytochrome c export following reoxygenation (Shiva et al., 2007; Chouchani et al., 2013).”
BackgroundSignaling and stress: The redox landscape in NOS2 biology
Thomas, D. D., Heinecke, J. L., Ridnour, L. A., Cheng, R. Y., Kesarwala, A. H., Switzer, C. H., McVicar, D. W., Roberts, D. D., Glynn, S., Fukuto, J. M., et al. (2015) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2015.06.002 · Cited by 150
Mitochondrial respiratory chain complexes as sources and targets of thiol-based redox-regulation
Dröse, S., Brandt, U., & Wittig, I. (2014) · Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics · doi:10.1016/j.bbapap.2014.02.006 · Cited by 155
Succinate metabolism: a new therapeutic target for myocardial reperfusion injury
Pell, V. R., Chouchani, E. T., Frezza, C., Murphy, M. P., & Krieg, T. (2016) · Cardiovascular Research · doi:10.1093/cvr/cvw100 · Cited by 149
“Downstream of succinate oxidation, the inhibition of the transition of Complex I to its active state at reperfusion will also prevent ROS production and has been shown frequently to protect against IR injury.(28,41,42) Furthermore, a critical condition required for the occurrence of RET is the generation of a near-max…”
BackgroundSelf-citationHigh-resolution cryo-EM structures of respiratory complex I: Mechanism, assembly, and disease
Parey, K., Haapanen, O., Sharma, V., Köfeler, H. C., Züllig, T., Prinz, S., Siegmund, K., Wittig, I., Mills, D. J., Vonck, J., et al. (2019) · Science Advances · doi:10.1126/sciadv.aax9484 · Cited by 147
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Turn up the power - pharmacological activation of mitochondrial biogenesis in mouse models
Komen, J. C., & Thorburn, D. R. (2014) · British Journal of Pharmacology · doi:10.1111/bph.12413 · Cited by 149
“drial S-nitrosation of CI forms a major part of the mechanism underlying the protective effect of NO during ischaemic reperfusion, thereby forming a therapeutic target for the prevention of injury after infarct or stroke (Chouchani et al., 2013).”
BackgroundPost-translational modifications in mitochondria: protein signaling in the powerhouse
Stram, A. R., & Payne, R. M. (2016) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-016-2280-4 · Cited by 149
“This resulted in reduction in activity of CI and decreased ROS generation, which would be expected to contribute to the mechanism of cardioprotection [39, 59, 60].”
Mitochondria and aging: A role for the mitochondrial transition pore?
Panel, M., Ghaleh, B., & Morin, D. (2018) · Aging Cell · doi:10.1111/acel.12793 · Cited by 152
“complex I of the respiratory chain (Chouchani et al., 2013).”
Microfabricated perfusable cardiac biowire: a platform that mimics native cardiac bundle
Xiao, Y., Zhang, B., Liu, H., Miklas, J. W., Gagliardi, M., Pahnke, A., Thavandiran, N., Sun, Y., Simmons, C. A., Keller, G. M., et al. (2013) · Lab on a Chip · doi:10.1039/c3lc51123e · Cited by 150
Molecular Vehicles for Mitochondrial Chemical Biology and Drug Delivery
Jean, S. R., Tulumello, D. V., Wisnovsky, S., Lei, E. K., Pereira, M. P., & Kelley, S. O. (2014) · ACS Chemical Biology · doi:10.1021/cb400821p · Cited by 150
Daiber, A., Kuntić, M., Hahad, O., Delogu, L. G., Rohrbach, S., Lisa, F. D., Schulz, R., & Münzel, T. F. (2020) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2020.108662 · Cited by 143
Mitochondria as a therapeutic target for cardiac ischemia‑reperfusion injury (Review)
Marin, W., Marin, D., Ao, X., & Liu, Y. (2020) · International Journal of Molecular Medicine · doi:10.3892/ijmm.2020.4823 · Cited by 140
“Several thiol‐reactive agents can be used to lock complex I in the deactive state by thiol modification on Cys39, including S-nitrosation (-SH into -SNO) by S-nitrosothiols (MitoSNO) or sodium nitrite (NaNO2) (84,130), S-sulfenylation (-SH into -SOH) by H2O2 (131), S-glutathionylation (-SH into -SSG) by glutathione di…”
BackgroundMethodInfluentialIschemic A/D transition of mitochondrial complex I and its role in ROS generation
Dröse, S., Степанова, А., & Galkin, A. S. (2016) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2015.12.013 · Cited by 140
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Self-citationStructural basis for a complex I mutation that blocks pathological ROS production
Yin, Z., Burger, N., Kula‐Alwar, D., Aksentijević, D., Bridges, H. R., Prag, H. A., Grba, D. N., Viscomi, C. F., James, A. M., Mottahedin, A., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-20942-w · Cited by 132
Self-citationGould, N. S., Evans, P., Martínez-Acedo, P., Marino, S. M., Gladyshev, V. N., Carroll, K. S., & Ischiropoulos, H. (2015) · Chemistry & Biology · doi:10.1016/j.chembiol.2015.06.010 · Cited by 128
“Combined with the abundance of SNO proteins within cluster 2, which is highly populated with mitochondria localization and oxidoreductase activities, this fits well with the known cardioprotective effects of SNOduring ischemia and the role of SNO in fatty acid b-oxidation (Chouchani et al., 2013; Doulias et al., 2013b…”
BackgroundCharacterisation of the active/de-active transition of mitochondrial complex I
Babot, M., Birch, A., Labarbuta, P., & Galkin, A. S. (2014) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2014.02.018 · Cited by 135
“MitoSNO was found to nitrosate Cys-39 of the ND3 subunit and in-hibitcomplexIafterbutnotbeforeischaemiainanintactheartmodelof cardiac I/R [90].”
BackgroundMethodInfluentialAnalysis of ischemia/reperfusion injury in time‐zero biopsies predicts liver allograft outcomes
Ali, J. M., Davies, S. E., Brais, R. J., Randle, L. V., Klinck, J. R., Allison, M., Chen, Y., Pasea, L., Harper, S., & Pettigrew, G. J. (2014) · Liver Transplantation · doi:10.1002/lt.24072 · Cited by 131
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S-glutathionylation reactions in mitochondrial function and disease
Mailloux, R. J., & Willmore, W. G. (2014) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2014.00068 · Cited by 130
Structure of the Deactive State of Mammalian Respiratory Complex I
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Respiratory complex I — structure, mechanism and evolution
Parey, K., Wirth, C., Vonck, J., & Zickermann, V. (2020) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2020.01.004 · Cited by 127
A p38MAPK/MK2 signaling pathway leading to redox stress, cell death and ischemia/reperfusion injury
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“Chouchani ET, Methner C, Nadtochiy SM, Logan A, Pell VR, Ding S, James AM, Cocheme HM, Reinhold J, Lilley KS, et al: Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I. Nat Med 2013, 19:753–759.”
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Metadata
- Authors
- Chouchani, E. T., Methner, C., Nadtochiy, S. M., Logan, A., Pell, V. R., Ding, S., James, A. M., Cochemé, H. M., Reinhold, J., Lilley, K. S., Partridge, L., Fearnley, I. M., Robinson, A. J., Hartley, R. C., Smith, R. A. J., Krieg, T., Brookes, P. S., & Murphy, M. P.
- Affiliations
- MRC Mitochondrial Biology Unit (GB)
- Max Planck Society (DE)
- Corresponding author
- Murphy, Michael P
- ORCID
- Venue
- Nature Medicine
- Published
- 2013-05-26
- Volume
- 19
- Issue
- 6
- Pages
- 753-759
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC4019998
- OpenAlex
- W1994270731
- Semantic Scholar
- 97e1eb3beeba3f16e5a83fa5a94d80446f1bb0b7
- Cited by
- 619
- References
- 46
- Citations by year
- 2026: 19 · 2025: 38 · 2024: 39 · 2023: 31 · 2022: 42 · 2021: 51 · 2020: 59 · 2019: 37 · 2018: 60 · 2017: 50 · 2016: 60 · 2015: 54 · 2014: 58 · 2013: 20
- FWCI
- 47.86
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Spiral (Imperial College London) (submittedVersion)
- UEA Digital Repository (University of East Anglia) (submittedVersion)
- Funders
- Wellcome Trust (098565)
- British Heart Foundation (PG/12/42/29655)
- Canadian Institutes of Health Research
- Biotechnology and Biological Sciences Research Council (BB/I012923/1, BB/I012826/1, BB/I012923)
- National Heart, Lung, and Blood Institute (R01HL071158)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Ischemia and Reperfusion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Physiology (medical) › Nitric Oxide and Endothelin Effects
- Keywords
- S-nitrosylation, mitochondrial complex I, nitric oxide donors, myocardial ischemia-reperfusion injury, cardioprotection, reactive oxygen species, oxidative damage, mitochondrial respiratory chain, myocardial infarction, stroke
- MeSH terms
- Animals, Cysteine, Male, Mice, Inbred C57BL, Mitochondria, Heart, Myocardial Reperfusion Injury, Nitrosation, Reactive Oxygen Species, Protein Subunits, Mitochondrial Proteins, Electron Transport Complex I, Mice, Rats
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-10-06, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-06 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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