The Role of the Pyruvate Dehydrogenase Complex in the Development of Ischemic-Reperfusion Syndrome

Background. One of the key components of energy metabolism is the pyruvate dehydrogenase complex (PDC), the activity of which can be targeted by some cytoprotectors. However, their role remains unclear. It is known that the activation of the PDC in tumor cells leads to an inversion of anaerobic glycolysis with an increase in the generation of free radicals in the respiratory chain and a decrease in viability. At the same time, there is evidence of increased resistance of normal cells to hypoxia and reperfusion.
Objectives. Analysis of current information on the role of PDC in the development of pathologic biochemical changes in ischemic reperfusion syndrome and methods of metabolic correction using agents for regulating the activity of the considered multienzyme complex.
Methods. The bibliographical search was carried out across the eLIBRARY and PubMed databases with a selection of articles published over the past 10 years in the English and Russian languages, as well as some parts of fundamental works in the selected field, published more than 10 years. To be selected for bibliographical review, the article can be of any design, reflecting the ideas about the role of PDC in the development of pathologic biochemical changes in ischemic-reperfusion lesions of various organs and tissues.
Results. The bibliographical analysis indicates a decrease in the activity of PDC in myocardial tissue during a heart attack or heart failure, the activity of the enzyme in skeletal muscles decreases against the background of acute hypoxia. PDC activity also decreases under chronic stress and extensive muscular exercise. At the same time, the PDC activity remains at the normal level in the ischemic period, and the transition to the reperfusion period is accompanied by a sharp decrease in the activity of the multienzyme complex. The PDC inactivation occurring under these conditions can result from a damage by reactive oxygen species, as well as by regulatory control changes through phosphorylation/dephosphorylation. Assuming the key role of PDC in the development of energy exchange disorders against the ischemic-reperfusion injuries 2 main strategies might be offered for metabolic correction: 1) an increase in the activity of PDC (activator — sodium dichloroacetate) or compensation for its lack with substrates of the tricarboxylic acids (acetylcarnitine, β-ydroxybutyrate); 2) protection of PDC from damage (antioxidants).
Conclusion. The basis of energy exchange disorders in the reperfusion period is a decrease in PDC activity, and modification of its activity is a promising direction for metabolic prevention or correction of ischemic-reperfusion injures.

1. Thibodeau A., Geng X., Previch L.E., Ding Y. Pyruvate dehydrogenase complex in cerebral ischemia-reperfusion injury. Brain. Circ. 2016; 2(2): 61–66. DOI: 10.4103/2394-8108.186256

2. Golias T., Kery M., Radenkovic S., Papandreou I. Microenvironmental control of glucose metabolism in tumors by regulation of pyruvate dehydrogenase. Int. J. Cancer. 2019; 144(4): 674–686. DOI: 10.1002/ijc.31812

3. Stacpoole P.W. Therapeutic targeting of the pyruvate dehydrogenase complex/pyruvate dehydrogenase kinase (PDC/PDK) axis in cancer. J. Natl. Cancer Inst. 2017; 109(11): djx071. DOI: 10.1093/jnci/djx071

4. Handzlik M.K., Constantin-Teodosiu D., Greenhaff P.L., Cole M.A. Increasing cardiac pyruvate dehydrogenase flux during chronic hypoxia improves acute hypoxic tolerance. J. Physiol. 2018; 596(15): 3357–3369. DOI: 10.1113/JP275357

5. Park S., Jeon J.H., Min B.K., Ha C.M., Thoudam T., Park B.Y., Lee I.K. Role of the pyruvate dehydrogenase complex in metabolic remodeling: differential pyruvate dehydrogenase complex functions in metabolism. Diabetes. Metab. J. 2018; 42(4): 270–281. DOI: 10.4093/dmj.2018.0101

6. Patel M.S., Nemeria N.S., Furey W., Jordan F. The pyruvate dehydrogenase complexes: structure-based function and regulation. J. Biol. Chem. 2014; 289(24): 16615–16623. DOI: 10.1074/jbc.R114.563148

7. Fukushima A., Alrob O.A., Zhang L., Wagg C.S., Altamimi T., Rawat S., Rebeyka I.M., Kantor P.F., Lopaschuk G.D. Acetylation and succinylation contribute to maturational alterations in energy metabolism in the newborn heart. Am. J. Physiol. Heart. Circ. Physiol. 2016; 311(2): H347–Н363. DOI: 10.1152/ajpheart.00900.2015

8. Jha M.K., Jeon S., Suk K. Pyruvate Dehydrogenase Kinases in the Nervous System: Their Principal Functions in Neuronal-glial Metabolic Interaction and Neuro-metabolic Disorders. Curr. Neuropharmacol. 2012; 10(4): 393–403. DOI: 10.2174/157015912804143586

9. Kho A.R., Choi B.Y., Lee S.H., Hong D.K., Jeong J.H., Kang B.S., Kang D.H., Park K.H., Park J.B., Suh S.W. The effects of sodium dichloroacetate on mitochondrial dysfunction and neuronal death following hypoglycemia-induced injury. Cells. 2019; 8(5): 405. DOI: 10.3390/cells8050405

10. Blum J.I., Bijli K.M., Murphy T.C., Kleinhenz J.M., Hart C.M. Time-dependent PPARγ modulation of HIF-1α signaling in hypoxic pulmonary artery smooth muscle cells. Am. J. Med. Sci. 2016; 352(1): 71–79. DOI: 10.1016/j.amjms.2016.03.019

11. Echeverri Ruiz N.P., Mohan V., Wu J., Scott S., Kreamer M., Benej M., Golias T., Papandreou I., Denko N.C. Dynamic regulation of mitochondrial pyruvate metabolism is necessary for orthotopic pancreatic tumor growth. Cancer Metab. 2021; 9(1): 39. DOI: 10.1186/s40170-021-00275-4

12. Kim D.H., Chauhan S. The role of dichloroacetate in improving acute hypoxic tolerance and cardiac function: translation to failing hearts? J. Physiol. 2018; 596(15): 2967–2968. DOI: 10.1113/JP276217

13. Astratenkova, I.V., Rogozkin V.A. The role of acetylation/deacetylation of histones and transcription factors in regulating metabolism in skeletal muscles. Neuroscience and Behavioral Physiology. 2019; 49(3): 281–288. DOI 10.1007/s11055-019-00730-2

14. Chen J., Guccini I., Di Mitri D., Brina D., Revandkar A., Sarti M., Pasquini E., Alajati A., Pinton S., Losa M., Civenni G., Catapano C.V., Sgrignani J., Cavalli A., D’Antuono R., Asara J.M., Morandi A., Chiarugi P., Crotti S., Agostini M., Montopoli M., Masgras I., Rasola A., Garcia-Escudero R., Delaleu N., Rinaldi A., Bertoni F., Bono J., Carracedo A., Alimonti A. Compartmentalized activities of the pyruvate dehydrogenase complex sustain lipogenesis in prostate cancer. Nat. Genet. 2018; 50(2): 219–228. DOI: 10.1038/s41588-017-0026-3

15. Sutendra G., Kinnaird A., Dromparis P., Paulin R., Stenson T.H., Haromy A., Hashimoto K., Zhang N., Flaim E., Michelakis E.D. A nuclear pyruvate dehydrogenase complex is important for the generation of acetyl-CoA and histone acetylation. Cell. 2014; 158(1): 84–97. DOI: 10.1016/j.cell.2014.04.046

16. Dodd M.S., Atherton H.J., Carr C.A., Stuckey D.J., West J.A., Griffin J.L., Radda G.K., Clarke K., Heather L.C., Tyler D.J. Impaired in vivo mitochondrial Krebs cycle activity after myocardial infarction assessed using hyperpolarized magnetic resonance spectroscopy. Circ. Cardiovasc. Imaging. 2014; 7(6): 895–904. DOI: 10.1161/CIRCIMAGING.114.001857

17. Piao L., Fang Y.H., Kubler M.M., Donnino M.W., Sharp W.W. Enhanced pyruvate dehydrogenase activity improves cardiac outcomes in a murine model of cardiac arrest. PLoS One. 2017; 12(9): e0185046. DOI: 10.1371/journal.pone.0185046

18. Morales-Alamo D, Guerra B, Santana A, Martin-Rincon M, Gelabert-Rebato M, Dorado C., Calbet J.A.L. Skeletal muscle pyruvate dehydrogenase phosphorylation and lactate accumulation during sprint exercise in normoxia and severe acute hypoxia: effects of antioxidants. Front. Physiol. 2018; 9: 188. DOI: 10.3389/fphys.2018.00188

19. Parolin M.L., Spriet L.L., Hultman E., Hollidge-Horvat M.G., Jones N.L., Heigenhauser G.J. Regulation of glycogen phosphorylase and PDH during exercise in human skeletal muscle during hypoxia. Am. J. Physiol. Endocrinol. Metab. 2000; 278(3): E522–E534. DOI: 10.1152/ajpendo.2000.278.3.E522

20. Gudiksen A., Schwartz C.L., Bertholdt L., Joensen E., Knudsen J.G., Pilegaard H. Lack of Skeletal Muscle IL-6 Affects Pyruvate Dehydrogenase Activity at Rest and during Prolonged Exercise. PLoS One. 2016; 11(6): e0156460. DOI: 10.1371/journal.pone.0156460

21. Martin E., Rosenthal R.E., Fiskum G. Pyruvate dehydrogenase complex: metabolic link to ischemic brain injury and target of oxidative stress. J. Neurosci. Res. 2005; 79(1–2): 240–247. DOI: 10.1002/jnr.20293

22. Chepur S.V., Pluzhnikov N.N., Chubar O.V., Fateev I.V., Bakulina L.S., Litvinenko I.V., Shirjaeva A.I. Lactic Acid: Dynamics of Ideas about the Lactate Biology. Uspekhi Sovremennoi Biologii. 2021; 141 (3): 227–247 (In Russ., English abstract). DOI: 10.31857/S0042132421030042

23. Sheeran F.L., Angerosa J., Liaw N.Y., Cheung M.M., Pepe S. Adaptations in Protein Expression and Regulated Activity of Pyruvate Dehydrogenase Multienzyme Complex in Human Systolic Heart Failure. Oxid. Med. Cell. Longev. 2019; 2019: 4532592. DOI: 10.1155/2019/4532592

24. Lan R., Geng H., Singha P.K., Saikumar P., Bottinger E.P., Weinberg J.M., Venkatachalam M.A. Mitochondrial pathology and glycolytic shift during proximal tubule atrophy after ischemic AKI. J. Am. Soc. Nephrol. 2016; 27(11): 3356–3367. DOI: 10.1681/ASN.2015020177

25. Sharma G., Wu C.Y., Wynn R.M., Gui W., Malloy C.R., Sherry A.D., Chuang D.T., Khemtong C. Real-time hyperpolarized 13C magnetic resonance detects increased pyruvate oxidation in pyruvate dehydrogenase kinase 2/4-double knockout mouse livers. Sci. Rep. 2019; 9(1): 16480. DOI: 10.1038/s41598-019-52952-6

26. Sapir G., Shaul D., Lev-Cohain N., Sosna J., Gomori M.J., Katz-Brull R. LDH and PDH Activities in the Ischemic Brain and the Effect of Reperfusion-An Ex Vivo MR Study in Rat Brain Slices Using Hyperpolarized [1-13C]Pyruvate. Metabolites. 2021; 11(4): 210. DOI: 10.3390/metabo11040210

27. Lazzarino G., Amorini A.M., Signoretti S., Musumeci G., Lazzarino G., Caruso G., Pastore F.S., Di Pietro V., Tavazzi B., Belli A. Pyruvate Dehydrogenase and Tricarboxylic Acid Cycle Enzymes Are Sensitive Targets of Traumatic Brain Injury Induced Metabolic Derangement. Int. J. Mol. Sci. 2019; 20(22): 5774. DOI: 10.3390/ijms20225774

28. Suh S.W., Gum E.T., Hamby A.M., Chan P.H., Swanson R.A. Hypoglycemic neuronal death is triggered by glucose reperfusion and activation of neuronal NADPH oxidase. J. Clin. Invest. 2007; 117(4): 910–918. DOI: 10.1172/JCI30077

29. Kim J.H., Yoo B.H., Won S.J., Choi B.Y., Lee B.E., Kim I.Y., Kho A., Lee S.H., Sohn M., Suh S.W. Melatonin Reduces Hypoglycemia-Induced Neuronal Death in Rats. Neuroendocrinology. 2015; 102(4): 300–310. DOI: 10.1159/000434722

30. Eguchi K., Nakayama K. Prolonged hypoxia decreases nuclear pyruvate dehydrogenase complex and regulates the gene expression. Biochem. Biophys. Res. Commun. 2019; 520(1): 128–135. DOI: 10.1016/j.bbrc.2019.09.109

31. Jalal F.Y., Böhlke M., Maher T.J. Acetyl-L-carnitine reduces the infarct size and striatal glutamate outflow following focal cerebral ischemia in rats. Ann. NY Acad. Sci. 2010; 1199: 95–104. DOI: 10.1111/j.1749-6632.2009.05351.x

32. Scafidi S., Racz J., Hazelton J., McKenna M.C., Fiskum G. Neuroprotection by acetyl-L-carnitine after traumatic injury to the immature rat brain. Dev. Neurosci. 2010; 32(5–6): 480–487. DOI: 10.1159/000323178

33. Mathias R.A., Greco T.M., Oberstein A., Budayeva H.G., Chakrabarti R., Rowland E.A., Kang Y., Shenk T., Cristea I.M. Sirtuin 4 is a lipoamidase regulating pyruvate dehydrogenase complex activity. Cell. 2014; 159(7): 1615–1625. DOI: 10.1016/j.cell.2014.11.046

34. Mathias R.A., Greco T.M., Cristea I.M. Identification of Sirtuin4 (SIRT4) Protein Interactions: Uncovering Candidate Acyl-Modified Mitochondrial Substrates and Enzymatic Regulators. Methods Mol. Biol. 2016; 1436: 213–239. DOI: 10.1007/978-1-4939-3667-0_15

35. Petronilho F., Florentino D., Danielski L.G., Vieira L.C., Martins M.M., Vieira A., Bonfante S., Goldim M.P., Vuolo F. Alpha-Lipoic Acid Attenuates Oxidative Damage in Organs After Sepsis. Inflammation. 2016; 39(1): 357–365. DOI: 10.1007/s10753-015-0256-4

36. Dulhunty A.F., Wei-LaPierre L., Casarotto M.G., Beard N.A. Core skeletal muscle ryanodine receptor calcium release complex. Clin. Exp. Pharmacol. Physiol. 2017; 44(1): 3–12. DOI: 10.1111/1440-1681.12676

37. Geng X., Elmadhoun O., Peng C., Ji X., Hafeez A., Liu Z., Du H., Rafols J.A., Ding Y. Ethanol and normobaric oxygen: novel approach in modulating pyruvate dehydrogenase complex after severe transient and permanent ischemic stroke. Stroke. 2015; 46(2): 492–499. DOI: 10.1161/STROKEAHA.114.006994

38. Richards E.M., Rosenthal R.E., Kristian T., Fiskum G. Postischemic hyperoxia reduces hippocampal pyruvate dehydrogenase activity. Free. Radic. Biol. Med. 2006; 40(11): 1960–1970. DOI: 10.1016/j.freeradbiomed.2006.01.022

39. Brennan-Minnella A.M., Won S.J., Swanson R.A. NADPH oxidase-2: linking glucose, acidosis, and excitotoxicity in stroke. Antioxid. Redox. Signal. 2015; 22(2): 161–174. DOI: 10.1089/ars.2013.5767

40. Shen J., Rastogi R., Geng X., Ding Y. Nicotinamide adenine dinucleotide phosphate oxidase activation and neuronal death after ischemic stroke. Neural. Regen. Res. 2019; 14(6): 948–953. DOI: 10.4103/1673-5374.250568

41. Kalogeris T., Bao Y., Korthuis R.J. Mitochondrial reactive oxygen species: a double edged sword in ischemia/reperfusion vs preconditioning. Redox. Biol. 2014; 2: 702–714. DOI: 10.1016/j.redox.2014.05.006

42. Sharma P., Benford B., Li Z.Z., Ling G.S. Role of pyruvate dehydrogenase complex in traumatic brain injury and Measurement of pyruvate dehydrogenase enzyme by dipstick test. J. Emerg. Trauma. Shock. 2009; 2(2): 67–72. DOI: 10.4103/0974-2700.50739

43. Radi R. Protein tyrosine nitration: biochemical mechanisms and structural basis of functional effects. Acc. Chem. Res. 2013; 46(2): 550–559. DOI: 10.1021/ar300234c

44. Xing G., Ren M., O’Neill J.T., Verma A., Watson W.D. Controlled cortical impact injury and craniotomy result in divergent alterations of pyruvate metabolizing enzymes in rat brain. Exp. Neurol. 2012; 234(1): 31–38. DOI: 10.1016/j.expneurol.2011.12.007

45. Hong D.K., Kho A.R., Choi B.Y., Lee S.H., Jeong J.H., Lee S.H., Park K.H., Park J.B., Suh S.W. Combined Treatment With Dichloroacetic Acid and Pyruvate Reduces Hippocampal Neuronal Death After Transient Cerebral Ischemia. Front. Neurol. 2018; 9: 137. DOI: 10.3389/fneur.2018.00137

46. Churchill E.N., Murriel C.L., Chen C.H., Mochly-Rosen D., Szweda L.I. Reperfusion-induced translocation of deltaPKC to cardiac mitochondria prevents pyruvate dehydrogenase reactivation. Circ. Res. 2005; 97(1): 78–85. DOI: 10.1161/01.RES.0000173896.32522.6e

47. Semenza G.L. Regulation of metabolism by hypoxia-inducible factor 1. Cold. Spring. Harb. Symp. Quant. Biol. 2011; 76: 347–353. DOI: 10.1101/sqb.2011.76.010678

48. Li J., Yang Y.L., Li L.Z., Zhang L., Liu Q., Liu K., Li P., Liu B., Qi L.W. Succinate accumulation impairs cardiac pyruvate dehydrogenase activity through GRP91-dependent and independent signaling pathways: Therapeutic effects of ginsenoside Rb1. Biochim. Biophys. Acta. Mol. Basis. Dis. 2017; 1863(11): 2835–2847. DOI: 10.1016/j.bbadis.2017.07.017

49. Glushakova L.G., Judge S., Cruz A., Pourang D., Mathews C.E., Stacpoole P.W. Increased superoxide accumulation in pyruvate dehydrogenase complex deficient fibroblasts. Mol. Genet. Metab. 2011; 104(3): 255–260. DOI: 10.1016/j.ymgme.2011.07.023

50. Bowker-Kinley M.M., Davis W.I., Wu P., Harris R.A., Popov K.M. Evidence for existence of tissue-specific regulation of the mammalian pyruvate dehydrogenase complex. Biochem. J. 1998; 329(Pt1): 191–196. DOI: 10.1042/bj3290191

51. Berendzen K., Theriaque D.W., Shuster J., Stacpoole P.W. Therapeutic potential of dichloroacetate for pyruvate dehydrogenase complex deficiency. Mitochondrion. 2006; 6(3): 126–135. DOI: 10.1016/j.mito.2006.04.001

52. Wang P., Chen M., Yang Z., Yu T., Zhu J., Zhou L., Lin J., Fang X., Huang Z., Jiang L., Tang W. Activation of Pyruvate Dehydrogenase Activity by Dichloroacetate Improves Survival and Neurologic Outcomes After Cardiac Arrest in Rats. Shock. 2018; 49(6): 704–711. DOI: 10.1097/SHK.0000000000000971

53. Tsymbalyuk I.Yu., Manuilov A.M., Popov K.A., Dyakov O.V. Metabolic correction of the ischemic-reperfusive liver damage against the background of its vascular exclusion in experimental conditions. Journal of Experimental and Clinical Surgery. 2017; 10(2): 130–136 (In Russ., English abstract). DOI: 10.18499/2070-478X-2017-10-2-130-136

54. Tsymbalyuk I.Yu., Manuilov A.M., Popov K.A., Basov A.A. Metabolic correction of the ischemia-reperfusive injury with sodium dichloroacetate in vascular isolation of the liver in experiment. Novosti Khirurgii. 2017; 25(5): 447–453 (In Russ., English abstract). DOI: 10.18484/2305-0047.2017.5.447

55. Maslov L.N., Naryzhnaia N.V., Podoksenov Yu.K., Gorbunov A.S., Zhang Y., Pei J.M. Role of Bradikynin in the Mechanism of Ischemic Preconditioning of the Heart. Prospects of Bradykinin Application in Cardiosurgical Praxis. Annals of the Russian Academy of Medical Sciences. 2015; 70 (2): 188–195 (In Russ., English abstract). DOI: 10.15690/vramn.v70i2.1312

56. Petrov S.A., Danilova A.O., Karpov L.M. The effect of a water-soluble vitamins on the activity of some enzymes in diabetes. Biomed. Khim. 2014; 60(6): 623–630 (In Russ., English abstract). DOI: 10.18097/pbmc20146006623

57. Shokri-Mashhadi N., Aliyari A., Hajhashemy Z., Saadat S., Rouhani M.H. Is it time to reconsider the administration of thiamine alone or in combination with vitamin C in critically ill patients? A meta-analysis of clinical trial studies. J. Intensive. Care. 2022; 10(1): 8. DOI: 10.1186/s40560-022-00594-8

58. Attaluri P., Castillo A., Edriss H., Nugent K. Thiamine Deficiency: An Important Consideration in Critically Ill Patients. Am. J. Med. Sci. 2018; 356(4): 382–390. DOI: 10.1016/j.amjms.2018.06.015

59. Lerner R.K., Pessach I., Rubinstein M., Paret G. Lactic Acidosis as Presenting Symptom of Thiamine Deficiency in Children with Hematologic Malignancy. J. Pediatr. Intensive. Care. 2017; 6(2): 132–135. DOI: 10.1055/s-0036-1587325

60. Asmaro K., Fu P., Ding Y. Neuroprotection & mechanism of ethanol in stroke and traumatic brain injury therapy: new prospects for an ancient drug. Curr. Drug. Targets. 2013; 14(1): 74–80. DOI: 10.2174/138945013804806505

61. Cai L., Stevenson J., Geng X., Peng C., Ji X., Xin R., Rastogi R., Sy C., Rafols J.A., Ding Y. Combining Normobaric Oxygen with Ethanol or Hypothermia Prevents Brain Damage from Thromboembolic Stroke via PKC-Akt-NOX Modulation. Mol. Neurobiol. 2017; 54(2): 1263–1277. DOI: 10.1007/s12035-016-9695-7

62. Boroujeni M.B., Khayat Z.K., Anbari K., Niapour A., Gholami M., Gharravi A.M. Coenzyme Q10 protects skeletal muscle from ischemia-reperfusion through the NF-kappa B pathway. Perfusion. 2017; 32(5): 372–377. DOI: 10.1177/0267659116683790

63. Connell B.J., Saleh M., Khan B.V., Saleh T.M. Lipoic acid protects against reperfusion injury in the early stages of cerebral ischemia. Brain Res. 2011; 1375: 128–136. DOI: 10.1016/j.brainres.2010.12.045

64. Ding Y., Zhang Y., Zhang W., Shang J., Xie Z., Chen C. Effects of Lipoic Acid on Ischemia-Reperfusion Injury. Oxid. Med. Cell. Longev. 2021; 2021: 5093216. DOI: 10.1155/2021/5093216

65. Mohammadrezaei Khorramabadi R., Anbari K., Salahshoor M.R., Alasvand M., Assadollahi V., Ghol ami M. Quercetin postconditioning attenuates gastrocnemius muscle ischemia/reperfusion injury in rats. J. Cell. Physiol. 2020; 235(12): 9876–9883. DOI: 10.1002/jcp.29801

66. Sarkaki A., Rashidi M., Ranjbaran M., Asareh Zadegan Dezfuli A., Shabaninejad Z., Behzad E., Adelipour M. Therapeutic Effects of Resveratrol on Ischemia-Reperfusion Injury in the Nervous System. Neurochem. Res. 2021; 46(12): 3085–3102. DOI: 10.1007/s11064-021-03412-z

67. Jankauskas S.S., Andrianova N.V., Alieva I.B., Prusov A.N., Matsievsky D.D., Zorova L.D., Pevzner I.B., Savchenko E.S., Pirogov Y.A., Silachev D.N., Plotnikov E.Y., Zorov D.B. Dysfunction of Kidney Endothelium after Ischemia/Reperfusion and Its Prevention by Mitochondria-Targeted Antioxidant. Biochemistry (Mosc). 2016; 81(12): 1538–1548. DOI: 10.1134/S0006297916120154

68. Ke B., Shen X.D., Zhang Y., Ji H., Gao F., Yue S., Kamo N., Zhai Y., Yamamoto M., Busuttil R.W., Kupiec-Weglinski J.W. KEAP1-NRF2 complex in ischemia-induced hepatocellular damage of mouse liver transplants. J. Hepatol. 2013; 59(6): 1200–1207. DOI: 10.1016/j.jhep.2013.07.016

69. Greco T., Fiskum G. Brain mitochondria from rats treated with sulforaphane are resistant to redox-regulated permeability transition. J. Bioenerg. Biomembr. 2010; 42(6): 491–749. DOI: 10.1007/s10863-010-9312-9

70. Singh A., Happel C., Manna S.K., Acquaah-Mensah G., Carrerero J., Kumar S., Nasipuri P., Krausz K.W., Wakabayashi N., Dewi R., Boros L.G., Gonzalez F.J., Gabrielson E., Wong K.K., Girnun G., Biswal S. Transcription factor NRF2 regulates miR-1 and miR-206 to drive tumorigenesis. J. Clin. Invest. 2013; 123(7): 2921–2934. DOI: 10.1172/JCI66353