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Resveratrol Inhibits Zinc Deficiency-Induced Mitophagy and Exerts Cardiac Cytoprotective Effects

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Abstract

Resveratrol (Res) possesses various beneficial effects, including cardioprotective, anti-inflammatory, anti-aging, and antioxidant properties. However, the precise mechanism underlying these effects remains unclear. Here we investigated the protective effects of resveratrol on cardiomyocytes, focusing on the role of Zn2+ and mitophagy. Using the MTT/lactate dehydrogenase assay, we found that addition of a zinc chelator TPEN for 4 h induced mitophagy and resulted in a significant reduction in cell viability, increased cytotoxicity, and apoptosis in H9c2 cells. Notably, resveratrol effectively mitigated these detrimental effects caused by TPEN. Similarly, Res inhibited the TPEN-induced expression of mitophagy-associated proteins, namely P62, LC3, NIX, TOM20, PINK1, and Parkin. The inhibitory action of resveratrol on mitophagy was abrogated by the mitophagy inhibitor 3-MA. Additionally, we discovered that silencing of the Mfn2 gene could reverse the inhibitory effects of resveratrol on mitophagy via the AMPK-Mfn2 axis, thereby preventing the opening of the mitochondrial permeability transition pore (mPTP). Collectively, our data suggest that Res can safeguard mitochondria protection by impeding mitophagy and averting mPTP opening through the AMPK-Mfn2 axis in myocardial cells.

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References

  1. Weiskirchen S, Weiskirchen R (2016) Resveratrol: how much wine do you have to drink to stay healthy? Adv Nutr 7(4):706–718. https://doi.org/10.3945/an.115.011627

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Breuss JM, Atanasov AG, Uhrin P (2019) Resveratrol and its effects on the vascular system. Int J Mol Sci 20(7):1523–1540. https://doi.org/10.3390/ijms20071523

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Li T, Chen L, Yu Y, Yang B, Li P, Tan XQ (2019) Resveratrol alleviates hypoxia/reoxygenation injury-induced mitochondrial oxidative stress in cardiomyocytes. Mol Med Rep 19(4):2774–2780. https://doi.org/10.3892/mmr.2019.9943

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Zhou TT, Wang XY, Huang J, Deng YZ, Qiu LJ, Liu HY, Xu XW, Ma ZX, Tang L, Chen HP (2020) Mitochondrial translocation of DJ-1 is mediated by Grp75: implication in cardioprotection of resveratrol against hypoxia/reoxygenation-induced oxidative stress. J Cardiovasc Pharmacol 75(4):305–313. https://doi.org/10.1097/fjc.0000000000000805

    Article  CAS  PubMed  Google Scholar 

  5. Huang CY, Ting WJ, Huang CY, Yang JY, Lin WT (2016) Resveratrol attenuated hydrogen peroxide-induced myocardial apoptosis by autophagic flux. Food Nutr Res 60:30511–30516. https://doi.org/10.3402/fnr.v60.30511

    Article  CAS  PubMed  Google Scholar 

  6. Jiang H, Wang G, Gu J, Xiao Y, Wang P, Huang X, Sha H, Wang Z, Ma Q (2022) Resveratrol inhibits the expression of RYR2 and is a potential treatment for pancreatic cancer. Naunyn Schmiedebergs Arch Pharmacol 395(3):315–324. https://doi.org/10.1007/s00210-022-02203-9

    Article  CAS  PubMed  Google Scholar 

  7. He Y, Fu Y, Xi M, Zheng H, Zhang Y, Liu Y, Zhao Y, Xi J, He Y (2020) Zn(2+) and mPTP mediate resveratrol-induced myocardial protection from endoplasmic reticulum stress. Metallomics: Integr Biometal Sci 12(2):290–300. https://doi.org/10.1039/c9mt00264b

    Article  CAS  Google Scholar 

  8. Feng L, Ren J, Li Y, Yang G, Kang L, Zhang S, Ma C, Li J, Liu J, Yang L, Qi Z (2019) Resveratrol protects against isoproterenol induced myocardial infarction in rats through VEGF-B/AMPK/eNOS/NO signalling pathway. Free Radical Res 53(1):82–93. https://doi.org/10.1080/10715762.2018.1554901

    Article  CAS  Google Scholar 

  9. Li T, Chen Z, Zhou Y, Li H, Xie J, Li L (2021) Resveratrol pretreatment inhibits myocardial apoptosis in rats following coronary microembolization via inducing the PI3K/Akt/GSK-3β signaling cascade. Drug Des Devel Ther 15:3821–3834. https://doi.org/10.2147/dddt.S323555

    Article  PubMed  PubMed Central  Google Scholar 

  10. Yang R, Dong H, Jia S, Yang Z (2022) Resveratrol as a modulatory of apoptosis and autophagy in cancer therapy. Clin Transl Oncol 24(7):1219–1230. https://doi.org/10.1007/s12094-021-02770-y

    Article  CAS  PubMed  Google Scholar 

  11. Ren X, Chen L, Xie J, Zhang Z, Dong G, Liang J, Liu L, Zhou H, Luo P (2017) Resveratrol ameliorates mitochondrial elongation via Drp1/Parkin/PINK1 signaling in senescent-like cardiomyocytes. Oxid Med Cell Longev 2017:4175353–4175372. https://doi.org/10.1155/2017/4175353

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Lixia Z, Wei S, Decheng B (2022) Protective effect of resveratrol on rat cardiomyocyte H9C2 cells injured by hypoxia/reoxygenation by regulating mitochondrial autophagy PTEN-induced putative kinase protein 1/Parkinson disease protein 2 signaling pathway. J Tradit Chin Med 42(2):176–186. https://doi.org/10.19852/j.cnki.jtcm.20220311.002

    Article  PubMed  Google Scholar 

  13. Begum F, Me HM, Christov M (2022) The role of zinc in cardiovascular disease. Cardiol Rev 30(2):100–108. https://doi.org/10.1097/crd.0000000000000382

    Article  PubMed  Google Scholar 

  14. Choi S, Liu X, Pan Z (2018) Zinc deficiency and cellular oxidative stress: prognostic implications in cardiovascular diseases. Acta Pharmacol Sin 39(7):1120–1132. https://doi.org/10.1038/aps.2018.25

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Pan Z, Choi S, Ouadid-Ahidouch H, Yang JM, Beattie JH, Korichneva I (2017) Zinc transporters and dysregulated channels in cancers. Front Biosci (Landmark Ed) 22(4):623–643. https://doi.org/10.2741/4507

    Article  CAS  PubMed  Google Scholar 

  16. Zhao H, Liu D, Yan Q, Bian X, Yu J, Wang J, Cheng X, Xu Z (2021) Endoplasmic reticulum stress/Ca(2+)-calmodulin-dependent protein kinase/signal transducer and activator of transcription 3 pathway plays a role in the regulation of cellular zinc deficiency in myocardial ischemia/reperfusion injury. Front Physiol 12:736920–736933. https://doi.org/10.3389/fphys.2021.736920

    Article  PubMed  Google Scholar 

  17. Yang Y, Zhou Q, Gao A, Chen L, Li L (2020) Endoplasmic reticulum stress and focused drug discovery in cardiovascular disease. Clin Chim Acta 504:125–137. https://doi.org/10.1016/j.cca.2020.01.031

    Article  CAS  PubMed  Google Scholar 

  18. Ochoa CD, Wu RF, Terada LS (2018) ROS signaling and ER stress in cardiovascular disease. Mol Aspects Med 63:18–29. https://doi.org/10.1016/j.mam.2018.03.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Pernas L, Scorrano L (2016) Mito-morphosis: mitochondrial fusion, fission, and cristae remodeling as key mediators of cellular function. Annu Rev Physiol 78:505–531. https://doi.org/10.1146/annurev-physiol-021115-105011

    Article  CAS  PubMed  Google Scholar 

  20. Copeland DE, Dalton AJ (1959) An association between mitochondria and the endoplasmic reticulum in cells of the pseudobranch gland of a teleost. J Biophys Biochem Cytol 5(3):393–396. https://doi.org/10.1083/jcb.5.3.393

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Vance JE (1990) Phospholipid synthesis in a membrane fraction associated with mitochondria. J Biol Chem 265(13):7248–7256

    Article  CAS  PubMed  Google Scholar 

  22. Perrone M, Caroccia N, Genovese I, Missiroli S, Modesti L, Pedriali G, Vezzani B, Vitto VAM, Antenori M, Lebiedzinska-Arciszewska M, Wieckowski MR, Giorgi C, Pinton P (2020) The role of mitochondria-associated membranes in cellular homeostasis and diseases. Int Rev Cell Mol Biol 350:119–196. https://doi.org/10.1016/bs.ircmb.2019.11.002

    Article  CAS  PubMed  Google Scholar 

  23. Gao P, Yan Z, Zhu Z (2020) Mitochondria-associated endoplasmic reticulum membranes in cardiovascular diseases. Front Cell Dev Biol 8:604240–604256. https://doi.org/10.3389/fcell.2020.604240

    Article  PubMed  PubMed Central  Google Scholar 

  24. Ni L, Yuan C (2021) The mitochondrial-associated endoplasmic reticulum membrane and its role in diabetic nephropathy. Oxid Med Cell Longev 2021:8054817–8054827. https://doi.org/10.1155/2021/8054817

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Li YE, Sowers JR, Hetz C, Ren J (2022) Cell death regulation by MAMs: from molecular mechanisms to therapeutic implications in cardiovascular diseases. Cell Death Dis 13(5):504–515. https://doi.org/10.1038/s41419-022-04942-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Hales KG, Fuller MT (1997) Developmentally regulated mitochondrial fusion mediated by a conserved, novel, predicted GTPase. Cell 90(1):121–129. https://doi.org/10.1016/s0092-8674(00)80319-0

    Article  CAS  PubMed  Google Scholar 

  27. Gomez-Suaga P, Paillusson S, Miller CCJ (2017) ER-mitochondria signaling regulates autophagy. Autophagy 13(7):1250–1251. https://doi.org/10.1080/15548627.2017.1317913

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Li A, Gao M, Liu B, Qin Y, Chen L, Liu H, Wu H, Gong G (2022) Mitochondrial autophagy: molecular mechanisms and implications for cardiovascular disease. Cell Death Dis 13(5):444–458. https://doi.org/10.1038/s41419-022-04906-6

    Article  PubMed  PubMed Central  Google Scholar 

  29. Salt IP, Hardie DG (2017) AMP-activated protein kinase: an ubiquitous signaling pathway with key roles in the cardiovascular system. Circ Res 120(11):1825–1841. https://doi.org/10.1161/circresaha.117.309633

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Diao RY, Gustafsson ÅB (2022) Mitochondrial quality surveillance: mitophagy in cardiovascular health and disease. Am J Physiol Cell Physiol 322(2):C218–C230. https://doi.org/10.1152/ajpcell.00360.2021

    Article  CAS  PubMed  Google Scholar 

  31. Wu S, Lu Q, Ding Y, Wu Y, Qiu Y, Wang P, Mao X, Huang K, Xie Z, Zou MH (2019) Hyperglycemia-driven inhibition of AMP-activated protein kinase α2 induces diabetic cardiomyopathy by promoting mitochondria-associated endoplasmic reticulum membranes in vivo. Circulation 139(16):1913–1936. https://doi.org/10.1161/circulationaha.118.033552

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Hu Y, Chen H, Zhang L, Lin X, Li X, Zhuang H, Fan H, Meng T, He Z, Huang H, Gong Q, Zhu D, Xu Y, He P, Li L, Feng D (2021) The AMPK-MFN2 axis regulates MAM dynamics and autophagy induced by energy stresses. Autophagy 17(5):1142–1156. https://doi.org/10.1080/15548627.2020.1749490

    Article  CAS  PubMed  Google Scholar 

  33. Yu H, Hong X, Liu L, Wu Y, Xie X, Fang G, Zhi S (2021) Cordycepin decreases ischemia/reperfusion injury in diabetic hearts via upregulating AMPK/Mfn2-dependent mitochondrial fusion. Front Pharmacol 12:754005–754018. https://doi.org/10.3389/fphar.2021.754005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Hussain A, Jiang W, Wang X, Shahid S, Saba N, Ahmad M, Dar A, Masood SU, Imran M, Mustafa A (2022) Mechanistic impact of Zinc deficiency in human development. Front Nutr 9:717064–717074. https://doi.org/10.3389/fnut.2022.717064

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Xing Z, He Q, Xiong Y, Zeng X (2021) Systematic Pharmacology Reveals the Antioxidative Stress and anti-inflammatory mechanisms of resveratrol intervention in myocardial ischemia-reperfusion injury. Evid Based Complement Alternat Med 2021:5515396–5515410. https://doi.org/10.1155/2021/5515396

    Article  PubMed  PubMed Central  Google Scholar 

  36. Lyu W, Li Q, Wang Y, Du C, Feng F, Chi H, Li Y, Liu W, Sun H (2021) Computational design of binder as the LC3-p62 protein-protein interaction. Bioorg Chem 115:105241. https://doi.org/10.1016/j.bioorg.2021.105241

    Article  CAS  PubMed  Google Scholar 

  37. Dorn GW 2nd, Kitsis RN (2015) The mitochondrial dynamism-mitophagy-cell death interactome: multiple roles performed by members of a mitochondrial molecular ensemble. Circ Res 116(1):167–182. https://doi.org/10.1161/circresaha.116.303554

    Article  CAS  PubMed  Google Scholar 

  38. Chen Y, Dorn GW 2nd (2013) PINK1-phosphorylated mitofusin 2 is a Parkin receptor for culling damaged mitochondria. Science (New York, N. Y.) 340(6131):471–5. https://doi.org/10.1126/science.1231031

    Article  ADS  CAS  PubMed  Google Scholar 

  39. Zhang P, Hu X, Xu X, Fassett J, Zhu G, Viollet B, Xu W, Wiczer B, Bernlohr DA, Bache RJ, Chen Y (2008) AMP activated protein kinase-alpha2 deficiency exacerbates pressure-overload-induced left ventricular hypertrophy and dysfunction in mice. Hypertension 52(5):918–924. https://doi.org/10.1161/hypertensionaha.108.114702

    Article  CAS  PubMed  Google Scholar 

  40. Xu X, Lu Z, Fassett J, Zhang P, Hu X, Liu X, Kwak D, Li J, Zhu G, Tao Y, Hou M, Wang H, Guo H, Viollet B, McFalls EO, Bache RJ, Chen Y (2014) Metformin protects against systolic overload-induced heart failure independent of AMP-activated protein kinase α2. Hypertension 63(4):723–728. https://doi.org/10.1161/hypertensionaha.113.02619

    Article  CAS  PubMed  Google Scholar 

  41. Wang B, Nie J, Wu L, Hu Y, Wen Z, Dong L, Zou MH, Chen C, Wang DW (2018) AMPKα2 protects against the development of heart failure by enhancing mitophagy via PINK1 phosphorylation. Circ Res 122(5):712–729. https://doi.org/10.1161/circresaha.117.312317

    Article  CAS  PubMed  Google Scholar 

  42. Morciano G, Bonora M, Campo G, Aquila G, Rizzo P, Giorgi C, Wieckowski MR, Pinton P (2017) Mechanistic role of mPTP in ischemia-reperfusion injury. Adv Exp Med Biol 982:169–189. https://doi.org/10.1007/978-3-319-55330-6_9

    Article  CAS  PubMed  Google Scholar 

  43. Li W, Liu B, Wang L, Liu J, Yang X, Zheng J (2021) Melatonin attenuates cardiac ischemia-reperfusion injury through modulation of IP3R-mediated mitochondria-ER contact. Oxid Med Cell Longev 2021:1370862–1370873. https://doi.org/10.1155/2021/1370862

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Funding

This work was supported by the Natural Science Foundation of China (No.82270303); the Natural Science Foundation of Hebei Province (No. H2020209172, H2021209061); the Department of Education of Hebei Province (No. ZD2020110).

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Authors and Affiliations

  1. School of Public Health, North China University of Science and Technology, Tangshan, 063000, China

    Pei Wang & Jinkun Xi

  2. Basic School of Medicine, Hebei Key Laboratory for Chronic Diseases, North China University of Science and Technology, Tangshan, China

    Ying Yang, Youcheng Hu & Luyao Huang

  3. Clinic School of Medicine, Hebei Key Laboratory of Medical-Industrial Integration Precision Medicine, North China University of Science and Technology, Tangshan, 063000, China

    Jiabao Guo, Tingting Ma & Jinkun Xi

  4. Affiliated Hospital, North China University of Science and Technology, Tangshan, 063000, China

    Jiabao Guo, Tingting Ma & Yonggui He

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  1. Pei Wang
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Contributions

PW: conception, methodology, reviewing, and editing original manuscript; YY: validation, data organization; JG: data curation, survey; TM: validation, data organization; YH: formal analysis; HL: visualization; JX and YH: project management, reviewing, and writing—original manuscript.

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Correspondence to Yonggui He or Jinkun Xi.

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Wang, P., Yang, Y., Guo, J. et al. Resveratrol Inhibits Zinc Deficiency-Induced Mitophagy and Exerts Cardiac Cytoprotective Effects. Biol Trace Elem Res 202, 1669–1682 (2024). https://doi.org/10.1007/s12011-023-03758-1

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