Skip to main content
Log in

RETRACTED ARTICLE: NR4A1 aggravates the cardiac microvascular ischemia reperfusion injury through suppressing FUNDC1-mediated mitophagy and promoting Mff-required mitochondrial fission by CK2α

  • Original Contribution
  • Published:
Basic Research in Cardiology Aims and scope Submit manuscript

This article was retracted on 15 June 2023

This article has been updated

Abstract

Mitochondrial fission and mitophagy are considered key processes involved in the pathogenesis of cardiac microvascular ischemia reperfusion (IR) injury although the upstream regulatory mechanism for fission and mitophagy still remains unclear. Herein, we reported that NR4A1 was significantly upregulated following cardiac microvascular IR injury, and its level was positively correlated with microvascular collapse, endothelial cellular apoptosis and mitochondrial damage. However, NR4A1-knockout mice exhibited resistance against the acute microvascular injury and mitochondrial dysfunction compared with the wild-type mice. Functional studies illustrated that IR injury increased NR4A1 expression, which activated serine/threonine kinase casein kinase2 α (CK2α). CK2α promoted phosphorylation of mitochondrial fission factor (Mff) and FUN14 domain-containing 1 (FUNDC1). Phosphorylated activation of Mff enhanced the cytoplasmic translocation of Drp1 to the mitochondria, leading to fatal mitochondrial fission. Excessive fission disrupted mitochondrial function and structure, ultimately triggering mitochondrial apoptosis. In addition, phosphorylated inactivation of FUNDC1 failed to launch the protective mitophagy process, resulting in the accumulation of damaged mitochondria and endothelial apoptosis. By facilitating Mff-mediated mitochondrial fission and FUNDC1-required mitophagy, NR4A1 disturbed mitochondrial homeostasis, enhanced endothelial apoptosis and provoked microvascular dysfunction. In summary, our data illustrated that NR4A1 serves as a novel culprit factor in cardiac microvascular IR injury that operates through synchronous elevation of fission and suppression of mitophagy. Novel therapeutic strategies targeting the balance among NR4A1, fission and mitophagy might provide survival advantage to microvasculature following IR stress.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

Change history

References

  1. Bahlawane C, Schmitz M, Letellier E, Arumugam K, Nicot N, Nazarov PV, Haan S (2017) Insights into ligand stimulation effects on gastro-intestinal stromal tumors signalling. Cell Signal 29:138–149. https://doi.org/10.1016/j.cellsig.2016.10.009

    Article  CAS  PubMed  Google Scholar 

  2. Banerjee K, Keasey MP, Razskazovskiy V, Visavadiya NP, Jia C, Hagg T (2017) Reduced FAK-STAT3 signaling contributes to ER stress-induced mitochondrial dysfunction and death in endothelial cells. Cell Signal 36:154–162. https://doi.org/10.1016/j.cellsig.2017.05.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Bei Y, Xu T, Lv D, Yu P, Xu J, Che L, Das A, Tigges J, Toxavidis V, Ghiran I, Shah R, Li Y, Zhang Y, Das S, Xiao J (2017) Exercise-induced circulating extracellular vesicles protect against cardiac ischemia-reperfusion injury. Basic Res Cardiol 112:38. https://doi.org/10.1007/s00395-017-0628-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Bhatelia K, Singh K, Prajapati P, Sripada L, Roy M, Singh R (2017) MITA modulated autophagy flux promotes cell death in breast cancer cells. Cell Signal 35:73–83. https://doi.org/10.1016/j.cellsig.2017.03.024

    Article  CAS  PubMed  Google Scholar 

  5. Brasacchio D, Alsop AE, Noori T, Lufti M, Iyer S, Simpson KJ, Bird PI, Kluck RM, Johnstone RW, Trapani JA (2017) Epigenetic control of mitochondrial cell death through PACS1-mediated regulation of BAX/BAK oligomerization. Cell Death Differ 24:961–970. https://doi.org/10.1038/cdd.2016.119

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Chen WR, Chen YD, Tian F, Yang N, Cheng LQ, Hu SY, Wang J, Yang JJ, Wang SF, Gu XF (2016) Effects of liraglutide on reperfusion injury in patients with ST-segment-elevation myocardial infarction. Circ Cardiovasc Imaging. https://doi.org/10.1161/CIRCIMAGING.116.005146

    Article  PubMed  PubMed Central  Google Scholar 

  7. Chen WR, Hu SY, Chen YD, Zhang Y, Qian G, Wang J, Yang JJ, Wang ZF, Tian F, Ning QX (2015) Effects of liraglutide on left ventricular function in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention. Am Heart J 170:845–854. https://doi.org/10.1016/j.ahj.2015.07.014

    Article  CAS  PubMed  Google Scholar 

  8. Chen Y, Wu R, Chen HZ, Xiao Q, Wang WJ, He JP, Li XX, Yu XW, Li L, Wang P, Wan XC, Tian XH, Li SJ, Yu X, Wu Q (2015) Enhancement of hypothalamic STAT3 acetylation by nuclear receptor Nur77 dictates leptin sensitivity. Diabetes 64:2069–2081. https://doi.org/10.2337/db14-1206

    Article  CAS  PubMed  Google Scholar 

  9. Cui Y, Liu S, Cui W, Gao D, Zhou W, Luo P (2017) Identification of potential biomarkers and therapeutic targets for human IgA nephropathy and hypertensive nephropathy by bioinformatics analysis. Mol Med Rep 16:3087–3094. https://doi.org/10.3892/mmr.2017.6996

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Das N, Mandala A, Naaz S, Giri S, Jain M, Bandyopadhyay D, Reiter RJ, Roy SS (2017) Melatonin protects against lipid-induced mitochondrial dysfunction in hepatocytes and inhibits stellate cell activation during hepatic fibrosis in mice. J Pineal Res. https://doi.org/10.1111/jpi.12404

    Article  PubMed  Google Scholar 

  11. Dong Y, Undyala VVR, Przyklenk K (2016) Inhibition of mitochondrial fission as a molecular target for cardioprotection: critical importance of the timing of treatment. Basic Res Cardiol 111:59. https://doi.org/10.1007/s00395-016-0578-x

    Article  CAS  PubMed  Google Scholar 

  12. Eitel I, de Waha S, Wohrle J, Fuernau G, Lurz P, Pauschinger M, Desch S, Schuler G, Thiele H (2014) Comprehensive prognosis assessment by CMR imaging after ST-segment elevation myocardial infarction. J Am Coll Cardiol 64:1217–1226. https://doi.org/10.1016/j.jacc.2014.06.1194

    Article  PubMed  Google Scholar 

  13. Fuhrmann DC, Brune B (2017) Mitochondrial composition and function under the control of hypoxia. Redox Biol 12:208–215. https://doi.org/10.1016/j.redox.2017.02.012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Garcia-Nino WR, Correa F, Rodriguez-Barrena JI, Leon-Contreras JC, Buelna-Chontal M, Soria-Castro E, Hernandez-Pando R, Pedraza-Chaverri J, Zazueta C (2017) Cardioprotective kinase signaling to subsarcolemmal and interfibrillar mitochondria is mediated by caveolar structures. Basic Res Cardiol 112:15. https://doi.org/10.1007/s00395-017-0607-4

    Article  CAS  PubMed  Google Scholar 

  15. Guarini G, Kiyooka T, Ohanyan V, Pung YF, Marzilli M, Chen YR, Chen CL, Kang PT, Hardwick JP, Kolz CL, Yin L, Wilson GL, Shokolenko I, Dobson JG Jr, Fenton R, Chilian WM (2016) Impaired coronary metabolic dilation in the metabolic syndrome is linked to mitochondrial dysfunction and mitochondrial DNA damage. Basic Res Cardiol 111:29. https://doi.org/10.1007/s00395-016-0547-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Heusch G (2016) The coronary circulation as a target of cardioprotection. Circ Res 118:1643–1658. https://doi.org/10.1161/CIRCRESAHA.116.308640

    Article  CAS  PubMed  Google Scholar 

  17. Hong H, Tao T, Chen S, Liang C, Qiu Y, Zhou Y, Zhang R (2017) MicroRNA-143 promotes cardiac ischemia-mediated mitochondrial impairment by the inhibition of protein kinase Cepsilon. Basic Res Cardiol 112:60. https://doi.org/10.1007/s00395-017-0649-7

    Article  CAS  PubMed  Google Scholar 

  18. Hu SY, Zhang Y, Zhu PJ, Zhou H, Chen YD (2017) Liraglutide directly protects cardiomyocytes against reperfusion injury possibly via modulation of intracellular calcium homeostasis. J Geriatr Cardiol 14:57–66. https://doi.org/10.11909/j.issn.1671-5411.2017.01.008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Jin Q, Li R, Hu N, Xin T, Zhu P, Hu S, Ma S, Zhu H, Ren J, Zhou H (2018) DUSP1 alleviates cardiac ischemia/reperfusion injury by suppressing the Mff-required mitochondrial fission and Bnip3-related mitophagy via the JNK pathways. Redox Biol 14:576–587. https://doi.org/10.1016/j.redox.2017.11.004

    Article  CAS  PubMed  Google Scholar 

  20. Jovancevic N, Dendorfer A, Matzkies M, Kovarova M, Heckmann JC, Osterloh M, Boehm M, Weber L, Nguemo F, Semmler J, Hescheler J, Milting H, Schleicher E, Gelis L, Hatt H (2017) Medium-chain fatty acids modulate myocardial function via a cardiac odorant receptor. Basic Res Cardiol 112:13. https://doi.org/10.1007/s00395-017-0600-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Kadlec AO, Beyer AM, Ait-Aissa K, Gutterman DD (2016) Mitochondrial signaling in the vascular endothelium: beyond reactive oxygen species. Basic Res Cardiol 111:26. https://doi.org/10.1007/s00395-016-0546-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Kanki T, Kurihara Y, Jin X, Goda T, Ono Y, Aihara M, Hirota Y, Saigusa T, Aoki Y, Uchiumi T, Kang D (2013) Casein kinase 2 is essential for mitophagy. EMBO Rep 14:788–794. https://doi.org/10.1038/embor.2013.114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Kim GS, Jung JE, Narasimhan P, Sakata H, Yoshioka H, Song YS, Okami N, Chan PH (2012) Release of mitochondrial apoptogenic factors and cell death are mediated by CK2 and NADPH oxidase. J Cereb Blood Flow Metab 32:720–730. https://doi.org/10.1038/jcbfm.2011.176

    Article  CAS  PubMed  Google Scholar 

  24. Ku DD (1982) Coronary vascular reactivity after acute myocardial ischemia. Science 218:576–578

    Article  CAS  PubMed  Google Scholar 

  25. Lehmann LH, Jebessa ZH, Kreusser MM, Horsch A, He T, Kronlage M, Dewenter M, Sramek V, Oehl U, Krebs-Haupenthal J, von der Lieth AH, Schmidt A, Sun Q, Ritterhoff J, Finke D, Volkers M, Jungmann A, Sauer SW, Thiel C, Nickel A, Kohlhaas M, Schafer M, Sticht C, Maack C, Gretz N, Wagner M, El-Armouche A, Maier LS, Londono JEC, Meder B, Freichel M, Grone HJ, Most P, Muller OJ, Herzig S, Furlong EEM, Katus HA, Backs J (2018) A proteolytic fragment of histone deacetylase 4 protects the heart from failure by regulating the hexosamine biosynthetic pathway. Nat Med 24:62–72. https://doi.org/10.1038/nm.4452

    Article  CAS  PubMed  Google Scholar 

  26. Lin C, Chao H, Li Z, Xu X, Liu Y, Hou L, Liu N, Ji J (2016) Melatonin attenuates traumatic brain injury-induced inflammation: a possible role for mitophagy. J Pineal Res 61:177–186. https://doi.org/10.1111/jpi.12337

    Article  CAS  PubMed  Google Scholar 

  27. Litchfield DW (2003) Protein kinase CK2: structure, regulation and role in cellular decisions of life and death. Biochem J 369:1–15. https://doi.org/10.1042/BJ20021469

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Meggio F, Pinna LA (2003) One-thousand-and-one substrates of protein kinase CK2? FASEB J 17:349–368. https://doi.org/10.1096/fj.02-0473rev

    Article  CAS  PubMed  Google Scholar 

  29. Oanh NTK, Park YY, Cho H (2017) Mitochondria elongation is mediated through SIRT1-mediated MFN1 stabilization. Cell Signal 38:67–75. https://doi.org/10.1016/j.cellsig.2017.06.019

    Article  CAS  PubMed  Google Scholar 

  30. Ong SB, Subrayan S, Lim SY, Yellon DM, Davidson SM, Hausenloy DJ (2010) Inhibiting mitochondrial fission protects the heart against ischemia/reperfusion injury. Circulation 121:2012–2022. https://doi.org/10.1161/CIRCULATIONAHA.109.906610

    Article  CAS  PubMed  Google Scholar 

  31. Pearson PJ, Schaff HV, Vanhoutte PM (1990) Acute impairment of endothelium-dependent relaxations to aggregating platelets following reperfusion injury in canine coronary arteries. Circ Res 67:385–393

    Article  CAS  PubMed  Google Scholar 

  32. Perdiz D, Lorin S, Leroy-Gori I, Pous C (2017) Stress-induced hyperacetylation of microtubule enhances mitochondrial fission and modulates the phosphorylation of Drp1 at (616)Ser. Cell Signal 39:32–43. https://doi.org/10.1016/j.cellsig.2017.07.020

    Article  CAS  PubMed  Google Scholar 

  33. Prieto-Dominguez N, Ordonez R, Fernandez A, Mendez-Blanco C, Baulies A, Garcia-Ruiz C, Fernandez-Checa JC, Mauriz JL, Gonzalez-Gallego J (2016) Melatonin-induced increase in sensitivity of human hepatocellular carcinoma cells to sorafenib is associated with reactive oxygen species production and mitophagy. J Pineal Res 61:396–407. https://doi.org/10.1111/jpi.12358

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Pryds K, Nielsen RR, Jorsal A, Hansen MS, Ringgaard S, Refsgaard J, Kim WY, Petersen AK, Botker HE, Schmidt MR (2017) Effect of long-term remote ischemic conditioning in patients with chronic ischemic heart failure. Basic Res Cardiol 112:67. https://doi.org/10.1007/s00395-017-0658-6

    Article  PubMed  Google Scholar 

  35. Randriamboavonjy V, Kyselova A, Elgheznawy A, Zukunft S, Wittig I, Fleming I (2017) Calpain 1 cleaves and inactivates prostacyclin synthase in mesenteric arteries from diabetic mice. Basic Res Cardiol 112:10. https://doi.org/10.1007/s00395-016-0596-8

    Article  CAS  PubMed  Google Scholar 

  36. Ronchi C, Torre E, Rizzetto R, Bernardi J, Rocchetti M, Zaza A (2017) Late sodium current and intracellular ionic homeostasis in acute ischemia. Basic Res Cardiol 112:12. https://doi.org/10.1007/s00395-017-0602-9

    Article  CAS  PubMed  Google Scholar 

  37. Rossello X, Riquelme JA, He Z, Taferner S, Vanhaesebroeck B, Davidson SM, Yellon DM (2017) The role of PI3 Kalpha isoform in cardioprotection. Basic Res Cardiol 112:66. https://doi.org/10.1007/s00395-017-0657-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Rovira-Llopis S, Banuls C, Diaz-Morales N, Hernandez-Mijares A, Rocha M, Victor VM (2017) Mitochondrial dynamics in type 2 diabetes: pathophysiological implications. Redox Biol 11:637–645. https://doi.org/10.1016/j.redox.2017.01.013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Salminen A, Kauppinen A, Kaarniranta K (2016) AMPK/Snf1 signaling regulates histone acetylation: impact on gene expression and epigenetic functions. Cell Signal 28:887–895. https://doi.org/10.1016/j.cellsig.2016.03.009

    Article  CAS  PubMed  Google Scholar 

  40. Shi C, Cai Y, Li Y, Li Y, Hu N, Ma S, Hu S, Zhu P, Wang W, Zhou H (2018) Yap promotes hepatocellular carcinoma metastasis and mobilization via governing cofilin/F-actin/lamellipodium axis by regulation of JNK/Bnip3/SERCA/CaMKII pathways. Redox Biol 14:59–71. https://doi.org/10.1016/j.redox.2017.08.013

    Article  CAS  PubMed  Google Scholar 

  41. Toyama EQ, Herzig S, Courchet J, Lewis TL Jr, Loson OC, Hellberg K, Young NP, Chen H, Polleux F, Chan DC, Shaw RJ (2016) Metabolism. AMP-activated protein kinase mediates mitochondrial fission in response to energy stress. Science 351:275–281. https://doi.org/10.1126/science.aab4138

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Van Nostrand JL, Bowen ME, Vogel H, Barna M, Attardi LD (2017) The p53 family members have distinct roles during mammalian embryonic development. Cell Death Differ 24:575–579. https://doi.org/10.1038/cdd.2016.128

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. van Tiel CM, Kurakula K, Koenis DS, van der Wal E, de Vries CJ (2012) Dual function of Pin1 in NR4A nuclear receptor activation: enhanced activity of NR4As and increased Nur77 protein stability. Biochim Biophys Acta 1823:1894–1904. https://doi.org/10.1016/j.bbamcr.2012.06.030

    Article  CAS  PubMed  Google Scholar 

  44. Vargas LA, Velasquez FC, Alvarez BV (2017) Compensatory role of the NBCn1 sodium/bicarbonate cotransporter on Ca(2+)-induced mitochondrial swelling in hypertrophic hearts. Basic Res Cardiol 112:14. https://doi.org/10.1007/s00395-017-0604-7

    Article  CAS  PubMed  Google Scholar 

  45. Wang WN, Zhang WL, Zhou GY, Ma FZ, Sun T, Su SS, Xu ZG (2016) Prediction of the molecular mechanisms and potential therapeutic targets for diabetic nephropathy by bioinformatics methods. Int J Mol Med 37:1181–1188. https://doi.org/10.3892/ijmm.2016.2527

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Xu A, Liu J, Liu P, Jia M, Wang H, Tao L (2014) Mitochondrial translocation of Nur77 induced by ROS contributed to cardiomyocyte apoptosis in metabolic syndrome. Biochem Biophys Res Commun 446:1184–1189. https://doi.org/10.1016/j.bbrc.2014.03.089

    Article  CAS  PubMed  Google Scholar 

  47. Yu E, Mercer J, Bennett M (2012) Mitochondria in vascular disease. Cardiovasc Res 95:173–182. https://doi.org/10.1093/cvr/cvs111

    Article  CAS  PubMed  Google Scholar 

  48. Zhang W, Ren H, Xu C, Zhu C, Wu H, Liu D, Wang J, Liu L, Li W, Ma Q, Du L, Zheng M, Zhang C, Liu J, Chen Q (2016) Hypoxic mitophagy regulates mitochondrial quality and platelet activation and determines severity of I/R heart injury. Elife. https://doi.org/10.7554/eLife.21407

    Article  PubMed  PubMed Central  Google Scholar 

  49. Zheng J, Wei CC, Hase N, Shi K, Killingsworth CR, Litovsky SH, Powell PC, Kobayashi T, Ferrario CM, Rab A, Aban I, Collawn JF, Dell’Italia LJ (2014) Chymase mediates injury and mitochondrial damage in cardiomyocytes during acute ischemia/reperfusion in the dog. PLoS One 9:e94732. https://doi.org/10.1371/journal.pone.0094732

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Zhou H, Du W, Li Y, Shi C, Hu N, Ma S, Wang W, Ren J (2018) Effects of melatonin on fatty liver disease: the role of NR4A1/DNA-PKcs/p53 pathway, mitochondrial fission, and mitophagy. J Pineal Res. https://doi.org/10.1111/jpi.12450

    Article  PubMed  Google Scholar 

  51. Zhou H, Hu S, Jin Q, Shi C, Zhang Y, Zhu P, Ma Q, Tian F, Chen Y (2017) Mff-dependent mitochondrial fission contributes to the pathogenesis of cardiac microvasculature ischemia/reperfusion injury via induction of mROS-mediated cardiolipin oxidation and HK2/VDAC1 disassociation-involved mPTP opening. J Am Heart Assoc. https://doi.org/10.1161/JAHA.116.005328

    Article  PubMed  PubMed Central  Google Scholar 

  52. Zhou H, Li D, Shi C, Xin T, Yang J, Zhou Y, Hu S, Tian F, Wang J, Chen Y (2015) Effects of Exendin-4 on bone marrow mesenchymal stem cell proliferation, migration and apoptosis in vitro. Sci Rep 5:12898. https://doi.org/10.1038/srep12898

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Zhou H, Li D, Zhu P, Hu S, Hu N, Ma S, Zhang Y, Han T, Ren J, Cao F, Chen Y (2017) Melatonin suppresses platelet activation and function against cardiac ischemia/reperfusion injury via PPARgamma/FUNDC1/mitophagy pathways. J Pineal Res. https://doi.org/10.1111/jpi.12438

    Article  PubMed  PubMed Central  Google Scholar 

  54. Zhou H, Ma Q, Zhu P, Ren J, Reiter RJ, Chen Y (2018) Protective role of melatonin in cardiac ischemia-reperfusion injury: from pathogenesis to targeted therapy. J Pineal Res. https://doi.org/10.1111/jpi.12471

    Article  PubMed  Google Scholar 

  55. Zhou H, Shi C, Hu S, Zhu H, Ren J, Chen Y (2018) BI1 is associated with microvascular protection in cardiac ischemia reperfusion injury via repressing Syk-Nox2-Drp1-mitochondrial fission pathways. Angiogenesis. https://doi.org/10.1007/s10456-018-9611-z

    Article  PubMed  PubMed Central  Google Scholar 

  56. Zhou H, Wang S, Zhu P, Hu S, Chen Y, Ren J (2017) Empagliflozin rescues diabetic myocardial microvascular injury via AMPK-mediated inhibition of mitochondrial fission. Redox Biol 15:335–346. https://doi.org/10.1016/j.redox.2017.12.019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Zhou H, Yang J, Xin T, Li D, Guo J, Hu S, Zhou S, Zhang T, Zhang Y, Han T, Chen Y (2014) Exendin-4 protects adipose-derived mesenchymal stem cells from apoptosis induced by hydrogen peroxide through the PI3K/Akt-Sfrp2 pathways. Free Radical Biol Med 77:363–375. https://doi.org/10.1016/j.freeradbiomed.2014.09.033

    Article  CAS  Google Scholar 

  58. Zhou H, Yang J, Xin T, Zhang T, Hu S, Zhou S, Chen G, Chen Y (2015) Exendin-4 enhances the migration of adipose-derived stem cells to neonatal rat ventricular cardiomyocyte-derived conditioned medium via the phosphoinositide 3-kinase/Akt-stromal cell-derived factor-1alpha/CXC chemokine receptor 4 pathway. Mol Med Rep 11:4063–4072. https://doi.org/10.3892/mmr.2015.3243

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Zhou H, Yue Y, Wang J, Ma Q, Chen Y (2018) Melatonin therapy for diabetic cardiomyopathy: a mechanism involving Syk-mitochondrial complex I-SERCA pathway. Cell Signal. https://doi.org/10.1016/j.cellsig.2018.03.012

    Article  PubMed  PubMed Central  Google Scholar 

  60. Zhou H, Zhang Y, Hu S, Shi C, Zhu P, Ma Q, Jin Q, Cao F, Tian F, Chen Y (2017) Melatonin protects cardiac microvasculature against ischemia/reperfusion injury via suppression of mitochondrial fission-VDAC1-HK2-mPTP-mitophagy axis. J Pineal Res. https://doi.org/10.1111/jpi.12413

    Article  PubMed  PubMed Central  Google Scholar 

  61. Zhou H, Zhu P, Guo J, Hu N, Wang S, Li D, Hu S, Ren J, Cao F, Chen Y (2017) Ripk3 induces mitochondrial apoptosis via inhibition of FUNDC1 mitophagy in cardiac IR injury. Redox Biol 13:498–507. https://doi.org/10.1016/j.redox.2017.07.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Zhou H, Zhu P, Wang J, Zhu H, Ren J, Chen Y (2018) Pathogenesis of cardiac ischemia reperfusion injury is associated with CK2alpha-disturbed mitochondrial homeostasis via suppression of FUNDC1-related mitophagy. Cell Death Differ. https://doi.org/10.1038/s41418-018-0086-7

    Article  PubMed  PubMed Central  Google Scholar 

  63. Zhu H, Jin Q, Li Y, Ma Q, Wang J, Li D, Zhou H, Chen Y (2018) Melatonin protected cardiac microvascular endothelial cells against oxidative stress injury via suppression of IP3R-[Ca(2+)]c/VDAC-[Ca(2+)]m axis by activation of MAPK/ERK signaling pathway. Cell Stress Chaperones 23:101–113. https://doi.org/10.1007/s12192-017-0827-4

    Article  CAS  PubMed  Google Scholar 

  64. Zong C, Qin D, Yu C, Gao P, Chen J, Lu S, Zhang Y, Liu Y, Yang Y, Pu Z, Li X, Fu Y, Guan Q, Wang X (2017) The stress-response molecule NR4A1 resists ROS-induced pancreatic beta-cells apoptosis via WT1. Cell Signal 35:129–139. https://doi.org/10.1016/j.cellsig.2017.03.012

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This study was supported by Grants from the National Natural Science Foundation of China (no. 81770237). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Author information

Authors and Affiliations

Authors

Contributions

HZ is involved in conception and design, performance of experiments, data analysis and interpretation, and manuscript writing. HZ, JW, and PJZ are involved in the development of methodology. HZ and JR are involved in the data acquisition. SYH and PJZ are involved in data analysis and interpretation. HZ and YDC are involved in study supervision and final approval of the manuscript.

Corresponding authors

Correspondence to Hao Zhou, Jun Ren or Yundai Chen.

Ethics declarations

Conflict of interest

The authors have declared that they have no conflicts of interest.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 2289 kb)

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhou, H., Wang, J., Zhu, P. et al. RETRACTED ARTICLE: NR4A1 aggravates the cardiac microvascular ischemia reperfusion injury through suppressing FUNDC1-mediated mitophagy and promoting Mff-required mitochondrial fission by CK2α. Basic Res Cardiol 113, 23 (2018). https://doi.org/10.1007/s00395-018-0682-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s00395-018-0682-1

Keywords

Navigation