miR‑335 promotes ferroptosis by targeting ferritin heavy chain 1 in <em>in vivo</em> and <em>in vitro</em> models of Parkinson's disease

Li,Xinrong; Si,Wenwen; Li,Zhan; Tian,Ye; Liu,Xuelei; Ye,Shanyu; Huang,Zifeng; Ji,Yichun; Zhao,Caiping; Hao,Xiaoqian; Chen,Dongfeng; Zhu,Meiling

doi:10.3892/ijmm.2021.4894

miR‑335 promotes ferroptosis by targeting ferritin heavy chain 1 in in vivo and in vitro models of Parkinson's disease

Authors:
- Xinrong Li
- Wenwen Si
- Zhan Li
- Ye Tian
- Xuelei Liu
- Shanyu Ye
- Zifeng Huang
- Yichun Ji
- Caiping Zhao
- Xiaoqian Hao
- Dongfeng Chen
- Meiling Zhu
View Affiliations

Affiliations: Traditional Chinese Medicine Innovation Research Center, Shenzhen Hospital of Integrated Traditional Chinese and Western Medicine, Shenzhen, Guangdong 518104, P.R. China, Guangdong Key Laboratory of Orthopedic Technology and Implant Materials, Key Laboratory of Trauma and Tissue Repair of Tropical Area of PLA, Hospital of Orthopedics, General Hospital of Southern Theater Command of PLA, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510010, P.R. China, Baoan Hospital of Traditional Chinese Medicine Affiliated to Guangzhou University of Traditional Chinese Medicine, Shenzhen, Guangdong 518101, P.R. China, Graduate School, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510405, P.R. China, Department of Anatomy, The Research Center of Basic Integrative Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, P.R. China
Published online on: February 23, 2021 https://doi.org/10.3892/ijmm.2021.4894
Article Number: 61
Copyright: © Li et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Parkinson's disease (PD) is a neurodegenerative disease characterized by the selective loss of dopaminergic neurons in the substantia nigra (SN). In a previous study, the authors demonstrated that ferritin heavy chain 1 (FTH1) inhibited ferroptosis in a model of 6‑hydroxydopamine (6‑OHDA)‑induced PD. However, whether and how microRNAs (miRNAs/miRs) modulate FTH1 in PD ferroptosis is not yet well understood. In the present study, in vivo and in vitro models of PD induced by 6‑OHDA were established. The results in vivo and in vitro revealed that the levels of the ferroptosis marker protein, glutathione peroxidase 4 (GPX4), and the PD marker protein, tyrosine hydroxylase (TH), were decreased in the model group, associated with a decreased FTH1 expression and the upregulation of miR‑335. In both the in vivo and in vitro models, miR‑335 mimic led to a lower FTH1 expression, exacerbated ferroptosis and an enhanced PD pathology. The luciferase 3'‑untranslated region reporter results identified FTH1 as the direct target of miR‑335. The silencing of FTH1 in 6‑OHDA‑stimulated cells enhanced the effects of miR‑335 on ferroptosis and promoted PD pathology. Mechanistically, miR‑335 enhanced ferroptosis through the degradation of FTH1 to increase iron release, lipid peroxidation and reactive oxygen species (ROS) accumulation, and to decrease mitochondrial membrane potential (MMP). On the whole, the findings of the present study reveal that miR‑335 promotes ferroptosis by targeting FTH1 in in vitro and in vivo models of PD, providing a potential therapeutic target for the treatment of PD.

View Figures

View References

1	Lei P, Bai T and Sun Y: Mechanisms of ferroptosis and relations with regulated cell death: A review. Front Physiol. 10:1392019. View Article : Google Scholar : PubMed/NCBI
2	Muhoberac BB, Baraibar MA and Vidal R: Iron loading-induced aggregation and reduction of iron incorporation in hetero- polymeric ferritin containing a mutant light chain that causes neurodegeneration. Biochim Biophys Acta. 1812:544–548. 2011. View Article : Google Scholar
3	Yang WS, SriRamaratnam R, Welsch ME, Shimada K, Skouta R, Viswanathan VS, Cheah JH, Clemons PA, Shamji AF, Clish CB, et al: Regulation of ferroptotic cancer cell death by GPX4. Cell. 156:317–331. 2014. View Article : Google Scholar : PubMed/NCBI
4	Yang WS and Stockwell BR: Ferroptosis: Death by lipid peroxidation. Trends Cell Biol. 26:165–176. 2016. View Article : Google Scholar :
5	Maiorino M, Conrad M and Ursini F: GPx4, lipid peroxidation, and cell death: Discoveries, rediscoveries, and open issues. Antioxid Redox Signal. 29:61–74. 2018. View Article : Google Scholar
6	Seibt TM, Proneth B and Conrad M: Role of GPX4 in ferroptosis and its pharmacological implication. Free Radic Biol Med. 133:144–152. 2019. View Article : Google Scholar
7	Forcina GC and Dixon SJ: GPX4 at the crossroads of lipid homeostasis and ferroptosis. Proteomics. 19:e18003112019. View Article : Google Scholar : PubMed/NCBI
8	Xie Y, Hou W, Song X, Yu Y, Huang J, Sun X, Kang R and Tang D: Ferroptosis: Process and function. Cell Death Differ. 23:369–379. 2016. View Article : Google Scholar : PubMed/NCBI
9	Knovich MA, Storey JA, Coffman LG, Torti SV and Torti FM: Ferritin for the clinician. Blood Rev. 23:95–104. 2009. View Article : Google Scholar :
10	Liu NQ, De Marchi T, Timmermans AM, Beekhof R, Trapman-Jansen AM, Foekens R, Look MP, van Deurzen CH, Span PN, Sweep FC, et al: Ferritin heavy chain in triple negative breast cancer: A favorable prognostic marker that relates to a cluster of differentiation 8 positive (CD8⁺) effector T-cell response. Mol Cell Proteomics. 13:1814–1827. 2014. View Article : Google Scholar : PubMed/NCBI
11	Shpyleva SI, Tryndyak VP, Kovalchuk O, Starlard-Davenport A, Chekhun VF, Beland FA and Pogribny IP: Role of ferritin alterations in human breast cancer cells. Breast Cancer Res Treat. 126:63–71. 2011. View Article : Google Scholar
12	Sammarco MC, Ditch S, Banerjee A and Grabczyk E: Ferritin L and H subunits are differentially regulated on a post-transcriptional level. J Biol Chem. 283:4578–4587. 2008. View Article : Google Scholar
13	Van Do B, Gouel F, Jonneaux A, Timmerman K, Gelé P, Pétrault M, Bastide M, Laloux C, Moreau C, Bordet R, et al: Ferroptosis, a newly characterized form of cell death in Parkinson's disease that is regulated by PKC. Neurobiol Dis. 94:169–178. 2016. View Article : Google Scholar
14	Tian Y, Lu J, Hao X, Li H, Zhang G, Liu X, Li X, Zhao C, Kuang W, Chen D and Zhu M: FTH1 inhibits ferroptosis through ferritinophagy in the 6-OHDA model of Parkinson's disease. Neurotherapeutics. 17:1796–1812. 2020. View Article : Google Scholar : PubMed/NCBI
15	Lu J, Liu X, Tian Y, Li H, Ren Z, Liang S, Zhang G, Zhao C, Li X, Wang T, et al: Moxibustion exerts a neuroprotective effect through antiferroptosis in Parkinson's disease. Evid Based Complement Alternat Med. 2019:27354922019. View Article : Google Scholar : PubMed/NCBI
16	Moreau C, Duce JA, Rascol O, Devedjian JC, Berg D, Dexter D, Cabantchik ZI, Bush AI and Devos D; FAIRPARK-II study group: Iron as a therapeutic target for Parkinson's disease. Mov Disord. 33:568–574. 2018. View Article : Google Scholar : PubMed/NCBI
17	Bonn D: Pumping iron in Parkinson's disease. Lancet. 347:16141996. View Article : Google Scholar : PubMed/NCBI
18	Guiney SJ, Adlard PA, Bush AI, Finkelstein DI and Ayton S: Ferroptosis and cell death mechanisms in Parkinson's disease. Neurochem Int. 104:34–48. 2017. View Article : Google Scholar : PubMed/NCBI
19	Biliński T, Krawiec Z, Liczmański A and Litwińska J: Is hydroxyl radical generated by the fenton reaction in vivo? Biochem Biophys Res Commun. 130:533–539. 1985. View Article : Google Scholar
20	Costello DJ, Walsh SL, Harrington HJ and Walsh CH: Concurrent hereditary haemochromatosis and idiopathic Parkinson's disease: A case report series. J Neurol Neurosurg Psychiatry. 75:631–633. 2004. View Article : Google Scholar : PubMed/NCBI
21	Miyajima H, Takahashi Y and Kono S: Aceruloplasminemia, an inherited disorder of iron metabolism. Biometals. 16:205–213. 2003. View Article : Google Scholar : PubMed/NCBI
22	Borie C, Gasparini F, Verpillat P, Bonnet AM, Agid Y, Hetet G, Brice A, Dürr A and Grandchamp B; French Parkinson's disease genetic study group: Association study between iron-related genes polymorphisms and Parkinson's disease. J Neurol. 249:801–804. 2002. View Article : Google Scholar : PubMed/NCBI
23	Rhodes SL, Buchanan DD, Ahmed I, Taylor KD, Loriot MA, Sinsheimer JS, Bronstein JM, Elbaz A, Mellick GD, Rotter JI and Ritz B: Pooled analysis of iron-related genes in Parkinson's disease: Association with transferrin. Neurobiol Dis. 62:172–178. 2014. View Article : Google Scholar
24	Ambros V: The functions of animal microRNAs. Nature. 431:350–355. 2004. View Article : Google Scholar : PubMed/NCBI
25	Bartel DP: MicroRNAs: Genomics, biogenesis, mechanism, and function. Cell. 116:281–297. 2004. View Article : Google Scholar : PubMed/NCBI
26	Bartel DP: MicroRNAs: Target recognition and regulatory functions. Cell. 136:215–233. 2009. View Article : Google Scholar : PubMed/NCBI
27	Bartel DP: Metazoan MicroRNAs. Cell. 173:20–51. 2018. View Article : Google Scholar : PubMed/NCBI
28	Su Y, Deng MF, Xiong W, Xie AJ, Guo J, Liang ZH, Hu B, Chen JG, Zhu X, Man HY, et al: MicroRNA-26a/death-associated protein kinase 1 signaling induces synucleinopathy and dopaminergic neuron degeneration in Parkinson's disease. Biol Psychiatry. 85:769–781. 2019. View Article : Google Scholar : PubMed/NCBI
29	Jin L, Wan W, Wang L, Wang C, Xiao J, Zhang F, Zhao J, Wang J, Zhan C and Zhong C: Elevated microRNA-520d-5p in the serum of patients with Parkinson's disease, possibly through regulation of cereloplasmin expression. Neurosci Lett. 687:88–93. 2018. View Article : Google Scholar : PubMed/NCBI
30	Asci R, Vallefuoco F, Andolfo I, Bruno M, De Falco L and Iolascon A: Trasferrin receptor 2 gene regulation by microRNA 221 in SH-SY5Y cells treated with MPP+ as Parkinson's disease cellular model. Neurosci Res. 77:121–127. 2013. View Article : Google Scholar : PubMed/NCBI
31	Rothblat DS, Schroeder JA and Schneider JS: Tyrosine hydroxylase and dopamine transporter expression in residual dopaminergic neurons: Potential contributors to spontaneous recovery from experimental Parkinsonism. J Neurosci Res. 65:254–266. 2001. View Article : Google Scholar : PubMed/NCBI
32	Deumens R, Blokland A and Prickaerts J: Modeling Parkinson's disease in rats: An evaluation of 6-OHDA lesions of the nigrostriatal pathway. Exp Neurol. 175:303–317. 2002. View Article : Google Scholar : PubMed/NCBI
33	Li Z, Lan X, Han R, Wang J, Huang Y, Sun J, Guo W and Chen H: miR-2478 inhibits TGFβ1 expression by targeting the transcriptional activation region downstream of the TGFβ1 promoter in dairy goats. Sci Rep. 7:426272017. View Article : Google Scholar
34	Lee SJ, Jeong JH, Kang SH, Kang J, Kim EA, Lee J, Jung JH, Park HY and Chae YS: MicroRNA-137 inhibits cancer progression by targeting Del-1 in triple-negative breast cancer cells. Int J Mol Sci. 20:61622019. View Article : Google Scholar
35	He H, Chen K, Wang F, Zhao L, Wan X, Wang L and Mo Z: miR-204-5p promotes the adipogenic differentiation of human adipose-derived mesenchymal stem cells by modulating DVL3 expression and suppressing Wnt/β-catenin signaling. Int J Mol Med. 35:1587–1595. 2015. View Article : Google Scholar : PubMed/NCBI
36	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar
37	Grayson M: Parkinson's disease. Nature. 538:S12016. View Article : Google Scholar : PubMed/NCBI
38	Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, Patel DN, Bauer AJ, Cantley AM, Yang WS, et al: Ferroptosis: An iron-dependent form of nonapoptotic cell death. Cell. 149:1060–1072. 2012. View Article : Google Scholar : PubMed/NCBI
39	Jiang H, Wang J, Rogers J and Xie J: Brain iron metabolism dysfunction in Parkinson's disease. Mol Neurobiol. 54:3078–3101. 2017. View Article : Google Scholar
40	Powers KM, Smith-Weller T, Franklin GM, Longstreth WT Jr, Swanson PD and Checkoway H: Dietary fats, cholesterol and iron as risk factors for Parkinson's disease. Parkinsonism Relat Disord. 15:47–52. 2009. View Article : Google Scholar :
41	Bellinger FP, Raman AV, Rueli RH, Bellinger MT, Dewing AS, Seale LA, Andres MA, Uyehara-Lock JH, White LR, Ross GW and Berry MJ: Changes in selenoprotein P in substantia nigra and putamen in Parkinson's disease. J Parkinsons Dis. 2:115–126. 2012. View Article : Google Scholar : PubMed/NCBI
42	Angelopoulou E, Paudel YN and Piperi C: miR-124 and Parkinson's disease: A biomarker with therapeutic potential. Pharmacol Res. 150:1045152019. View Article : Google Scholar : PubMed/NCBI
43	De Gregorio R: Pulcrano S, De Sanctis C, Volpicelli F, Guatteo E, von Oerthel L, Latagliata EC, Esposito R, Piscitelli RM, Perrone-Capano C, et al miR-34b/c regulates wnt1 and enhances mesencephalic dopaminergic neuron differentiation. Stem Cell Rep. 10:1237–1250. 2018. View Article : Google Scholar
44	Luo M, Wu L, Zhang K, Wang H, Zhang T, Gutierrez L, O'Connell D, Zhang P, Li Y, Gao T, et al: miR-137 regulates ferroptosis by targeting glutamine transporter SLC1A5 in melanoma. Cell Death Differ. 25:1457–1472. 2018. View Article : Google Scholar : PubMed/NCBI
45	Sangokoya C, Doss JF and Chi JT: Iron-responsive miR-485-3p regulates cellular iron homeostasis by targeting ferroportin. PLoS Genet. 9:e10034082013. View Article : Google Scholar : PubMed/NCBI
46	Poewe W, Bergmann L, Kukreja P, Robieson WZ and Antonini A: Levodopa-carbidopa intestinal gel monotherapy: GLORIA registry demographics, efficacy, and safety. J Parkinsons Dis. 9:531–541. 2019. View Article : Google Scholar : PubMed/NCBI