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Volume 24, Issue 12
  • ISSN: 1566-5240
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Abstract

Objectives

The degeneration of dopaminergic (DA) neurons has emerged as a crucial pathological characteristic in Parkinson’s disease (PD). To enrich the related knowledge, we aimed to explore the impact of the METTL14-TRAF6-cGAS-STING axis in mitochondrial dysfunction and ferroptosis underlying DA neuron degeneration.

Methods

1-methyl-4-phenylpyridinium ion (MPP+) was used to treat DA neuron MN9D to develop the PD cell models. Afterward, a cell counting kit, flow cytometer, DCFH-DA fluorescent probe, and Dipyrromethene Boron Difluoride staining were utilized to measure the cell viability, iron concentration, ROS level, and lipid peroxidation, respectively. Meanwhile, the mitochondrial ultrastructure, the activity of mitochondrial respiratory chain complexes, and levels of malondialdehyde and glutathione were monitored. In addition, reverse transcription-quantitative polymerase chain reaction and western blot assays were adopted to measure the expression of related genes. cGAS ubiquitylation and TRAF6 messenger RNA (mRNA) N6-methyladenosine (m6A) levels, the linkages among METTL14, TRAF6, and the cGAS-STING pathway were also evaluated.

Results

METTL14 expression was low, and TRAF6 expression was high after MPP+ treatment. In MPP+-treated MN9D cells, METTL14 overexpression reduced ferroptosis, ROS generation, mitochondrial injury, and oxidative stress (OS) and enhanced mitochondrial membrane potentials. TRAF6 overexpression had promoting impacts on mitochondrial dysfunction and ferroptosis in MPP+-treated MN9D cells, which was reversed by further overexpression of METTL14. Mechanistically, METTL14 facilitated the m6A methylation of TRAF6 mRNA to down-regulate TRAF6 expression, thus inactivating the cGAS-STING pathway.

Conclusion

METTL14 down-regulated TRAF6 expression through TRAF6 m6A methylation to inactivate the cGAS-STING pathway, thereby relieving mitochondrial dysfunction and ferroptosis in DA neurons.

© 2024 Bentham Science Publishers
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2024-12-01
2024-11-22

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References

  1. TolosaE. GarridoA. ScholzS.W. PoeweW. Challenges in the diagnosis of Parkinson’s disease.Lancet Neurol.202120538539710.1016/S1474‑4422(21)00030‑2 33894193
     [Google Scholar]
  2. LotankarS. PrabhavalkarK.S. BhattL.K. Biomarkers for parkinson’s disease: Recent advancement.Neurosci. Bull.201733558559710.1007/s12264‑017‑0183‑5 28936761
     [Google Scholar]
  3. RajanS. KaasB. Parkinson’s disease: Risk factor modification and prevention.Semin. Neurol.202242562663810.1055/s‑0042‑1758780 36427528
     [Google Scholar]
  4. MurataH. BarnhillL.M. BronsteinJ.M. Air pollution and the risk of parkinson’s disease: A review.Mov. Disord.202237589490410.1002/mds.28922 35043999
     [Google Scholar]
  5. BalestrinoR. SchapiraA.H.V. Parkinson disease.Eur. J. Neurol.2020271274210.1111/ene.14108 31631455
     [Google Scholar]
  6. ReichS.G. SavittJ.M. Parkinson’s disease.Med. Clin. North Am.2019103233735010.1016/j.mcna.2018.10.014 30704685
     [Google Scholar]
  7. MacdonaldR. BarnesK. HastingsC. MortiboysH. Mitochondrial abnormalities in Parkinson’s disease and Alzheimer’s disease: Can mitochondria be targeted therapeutically?Biochem. Soc. Trans.201846489190910.1042/BST20170501 30026371
     [Google Scholar]
  8. BurbullaL.F. SongP. MazzulliJ.R. Dopamine oxidation mediates mitochondrial and lysosomal dysfunction in Parkinson’s disease.Science201735763571255126110.1126/science.aam9080 28882997
     [Google Scholar]
  9. ZhaoT WangJ WuY Increased m6A modification of RNA methylation related to the inhibition of demethylase FTO contributes to MEHP-induced Leydig cell injury.Environ Pollut2021268(Pt A)11562710.1016/j.envpol.2020.115627
     [Google Scholar]
  10. BerulavaT. BuchholzE. ElerdashviliV. Changes in m6A RNA methylation contribute to heart failure progression by modulating translation.Eur. J. Heart Fail.2020221546610.1002/ejhf.1672 31849158
     [Google Scholar]
  11. WangJ. WangK. LiuW. CaiY. JinH. m6A mRNA methylation regulates the development of gestational diabetes mellitus in Han Chinese women.Genomics202111331048105610.1016/j.ygeno.2021.02.016 33667648
     [Google Scholar]
  12. ZhangY. YangY. Effects of m6A RNA methylation regulators on endometrial cancer.J. Clin. Lab. Anal.2021359e2394210.1002/jcla.23942 34347888
     [Google Scholar]
  13. ZhangN. DingC. ZuoY. PengY. ZuoL. N6-methyladenosine and neurological diseases.Mol. Neurobiol.20225931925193710.1007/s12035‑022‑02739‑0 35032318
     [Google Scholar]
  14. MengL. LinH. HuangX. WengJ. PengF. WuS. METTL14 suppresses pyroptosis and diabetic cardiomyopathy by downregulating TINCR lncRNA.Cell Death Dis.20221313810.1038/s41419‑021‑04484‑z 35013106
     [Google Scholar]
  15. GaoG. DuanY. ChangF. ZhangT. HuangX. YuC. METTL14 promotes apoptosis of spinal cord neurons by inducing EEF1A2 m6A methylation in spinal cord injury.Cell Death Discov.2022811510.1038/s41420‑021‑00808‑2 35013140
     [Google Scholar]
  16. TengY. LiuZ. ChenX. Conditional deficiency of m6A methyltransferase Mettl14 in substantia nigra alters dopaminergic neuron function.J. Cell. Mol. Med.202125178567857210.1111/jcmm.16740 34288397
     [Google Scholar]
  17. OuyangH. ZhangJ. ChiD. The YTHDF1–TRAF6 pathway regulates the neuroinflammatory response and contributes to morphine tolerance and hyperalgesia in the periaqueductal gray.J. Neuroinflammation202219131010.1186/s12974‑022‑02672‑y 36550542
     [Google Scholar]
  18. LuY. JiangB.C. CaoD.L. TRAF6 upregulation in spinal astrocytes maintains neuropathic pain by integrating TNF-α and IL-1β signaling.Pain2014155122618262910.1016/j.pain.2014.09.027 25267210
     [Google Scholar]
  19. ZucchelliS. CodrichM. MarcuzziF. TRAF6 promotes atypical ubiquitination of mutant DJ-1 and alpha-synuclein and is localized to Lewy bodies in sporadic Parkinson’s disease brains.Hum. Mol. Genet.201019193759377010.1093/hmg/ddq290 20634198
     [Google Scholar]
  20. KwonJ. BakhoumS.F. The cytosolic DNA-sensing cGAS–STING pathway in cancer.Cancer Discov.2020101263910.1158/2159‑8290.CD‑19‑0761 31852718
     [Google Scholar]
  21. DecoutA. KatzJ.D. VenkatramanS. AblasserA. The cGAS–STING pathway as a therapeutic target in inflammatory diseases.Nat. Rev. Immunol.202121954856910.1038/s41577‑021‑00524‑z 33833439
     [Google Scholar]
  22. ChenQ. SunL. ChenZ.J. Regulation and function of the cGAS–STING pathway of cytosolic DNA sensing.Nat. Immunol.201617101142114910.1038/ni.3558 27648547
     [Google Scholar]
  23. SzegoE.M. MalzL. BernhardtN. Rösen-WolffA. FalkenburgerB.H. LukschH. Constitutively active STING causes neuroinflammation and degeneration of dopaminergic neurons in mice.eLife202211e8194310.7554/eLife.81943 36314770
     [Google Scholar]
  24. ChenX. ChenY. Ubiquitination of cGAS by TRAF6 regulates anti-DNA viral innate immune responses.Biochem. Biophys. Res. Commun.2019514365966410.1016/j.bbrc.2019.05.022 31078259
     [Google Scholar]
  25. AyukS.M. AbrahamseH. HoureldN.N. The role of photobiomodulation on gene expression of cell adhesion molecules in diabetic wounded fibroblasts in vitro.J. Photochem. Photobiol. B201616136437410.1016/j.jphotobiol.2016.05.027
     [Google Scholar]
  26. DaiH.Y. ChangM.X. SunL. HOTAIRM1 knockdown reduces MPP + -induced oxidative stress injury of SH-SY5Y cells by activating the Nrf2/HO-1 pathway.Transl. Neurosci.20231412022029610.1515/tnsci‑2022‑0296 37529170
     [Google Scholar]
  27. LiuJ. EckertM.A. HaradaB.T. m6A mRNA methylation regulates AKT activity to promote the proliferation and tumorigenicity of endometrial cancer.Nat. Cell Biol.20182091074108310.1038/s41556‑018‑0174‑4 30154548
     [Google Scholar]
  28. WeintraubD. AarslandD. BiundoR. DobkinR. GoldmanJ. LewisS. Management of psychiatric and cognitive complications in Parkinson’s disease.BMJ2022379e06871810.1136/bmj‑2021‑068718
     [Google Scholar]
  29. MollenhauerB. von ArnimC.A.F. Toward preventing Parkinson’s disease.Science2022377660881881910.1126/science.add7162 35981039
     [Google Scholar]
  30. PanickerN. KamT.I. WangH. Neuronal NLRP3 is a parkin substrate that drives neurodegeneration in Parkinson’s disease.Neuron20221101524222437.e910.1016/j.neuron.2022.05.009 35654037
     [Google Scholar]
  31. HeidariA. YazdanpanahN. RezaeiN. The role of Toll-like receptors and neuroinflammation in Parkinson’s disease.J. Neuroinflammation202219113510.1186/s12974‑022‑02496‑w 35668422
     [Google Scholar]
  32. LiuM. LiuC. XiaoX. Role of upregulation of the K ATP channel subunit SUR1 in dopaminergic neuron degeneration in Parkinson’s disease.Aging Cell2022215e1361810.1111/acel.13618 35441806
     [Google Scholar]
  33. SunY. HeL. WangW. Activation of Atg7-dependent autophagy by a novel inhibitor of the Keap1-Nrf2 protein-protein interaction from Penthorum chinense Pursh. attenuates 6-hydroxydopamine-induced ferroptosis in zebrafish and dopaminergic neurons.Food Funct.202213147885790010.1039/D2FO00357K 35776077
     [Google Scholar]
  34. HuangL. BianM. ZhangJ. JiangL. Iron metabolism and ferroptosis in peripheral nerve injury.Oxid. Med. Cell. Longev.2022591821810.1155/2022/5918218
     [Google Scholar]
  35. RazaC. AnjumR. ShakeelN.U.A. Parkinson’s disease: Mechanisms, translational models and management strategies.Life Sci.20192267790
     [Google Scholar]
  36. CogliatiS. LorenziI. RigoniG. CaicciF. SorianoM.E. Regulation of mitochondrial electron transport chain assembly.J. Mol. Biol.2018430244849487310.1016/j.jmb.2018.09.016 30292820
     [Google Scholar]
  37. MahalanobishS. DuttaS. SahaS. SilP.C. Melatonin induced suppression of ER stress and mitochondrial dysfunction inhibited NLRP3 inflammasome activation in COPD mice.Food Chem. Toxicol.20201441158810.1016/j.fct.2020.111588
     [Google Scholar]
  38. ChenQ. HuangX. LiR. lncRNA MALAT1/miR-205-5p axis regulates MPP+-induced cell apoptosis in MN9D cells by directly targeting LRRK2.Am. J. Transl. Res.2018102563572 29511451
     [Google Scholar]
  39. FanH.N. ChenZ.Y. ChenX.Y. METTL14-mediated m6A modification of circORC5 suppresses gastric cancer progression by regulating miR-30c-2-3p/AKT1S1 axis.Mol. Cancer20222115110.1186/s12943‑022‑01521‑z 35164771
     [Google Scholar]
  40. ChenX. XuM. XuX. METTL14-mediated N6-methyladenosine modification of SOX4 mRNA inhibits tumor metastasis in colorectal cancer.Mol. Cancer202019110610.1186/s12943‑020‑01220‑7 32552762
     [Google Scholar]
  41. WengY.L. WangX. AnR. Epitranscriptomic m6A regulation of axon regeneration in the adult mammalian nervous system.Neuron2018972313.e62510.1016/j.neuron.2017.12.036 29346752
     [Google Scholar]
  42. ZhangK. LiP. JiaY. LiuM. JiangJ. Non-coding RNA and n6-methyladenosine modification play crucial roles in neuropathic pain.Front. Mol. Neurosci.202215100801810.3389/fnmol.2022.1002018
     [Google Scholar]
  43. QiL. HuH. WangY. New insights into the central sympathetic hyperactivity post‐myocardial infarction: Roles of METTL3‐mediated m 6 A methylation.J. Cell. Mol. Med.20222641264128010.1111/jcmm.17183 35040253
     [Google Scholar]
  44. ChenX. YuC. GuoM. Down-regulation of m6A mRNA methylation is involved in dopaminergic neuronal death.ACS Chem. Neurosci.20191052355236310.1021/acschemneuro.8b00657 30835997
     [Google Scholar]
  45. DuJ. SarkarR. LiY. N6-adenomethylation of GsdmC is essential for Lgr5+ stem cell survival to maintain normal colonic epithelial morphogenesis.Dev. Cell2022571619761994.e810.1016/j.devcel.2022.07.006 35917813
     [Google Scholar]
  46. FanZ. YangG. ZhangW. Hypoxia blocks ferroptosis of hepatocellular carcinoma via suppression of METTL14 triggered YTHDF2‐dependent silencing of SLC7A11.J. Cell. Mol. Med.20212521101971021210.1111/jcmm.16957 34609072
     [Google Scholar]
  47. DouY. TianX. ZhangJ. WangZ. ChenG. Roles of TRAF6 in central nervous system.Curr. Neuropharmacol.20181691306131310.2174/1570159X16666180412094655 29651950
     [Google Scholar]
  48. GuoB. ZuoZ. DiX. Salidroside attenuates HALI via IL-17A-mediated ferroptosis of alveolar epithelial cells by regulating Act1-TRAF6-p38 MAPK pathway.Cell Commun. Signal.202220118310.1186/s12964‑022‑00994‑1 36411467
     [Google Scholar]
  49. ArnoultD. SoaresF. TattoliI. GirardinS.E. Mitochondria in innate immunity.EMBO Rep.201112990191010.1038/embor.2011.157 21799518
     [Google Scholar]
  50. MaC. LiuY. LiS. Microglial cGAS drives neuroinflammation in the MPTP mouse models of Parkinson’s disease.CNS Neurosci. Ther.20232972018203510.1111/cns.14157 36914567
     [Google Scholar]
  51. HinkleJ.T. PatelJ. PanickerN. STING mediates neurodegeneration and neuroinflammation in nigrostriatal α-synucleinopathy.Proc. Natl. Acad. Sci.202211915e211881911910.1073/pnas.2118819119 35394877
     [Google Scholar]
/content/journals/cmm/10.2174/0115665240263859231018110107
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METTL14 Regulates the m6A Modification of TRAF6 to Suppress Mitochondrial Dysfunction and Ferroptosis in Dopaminergic Neurons via the cGAS-STING Pathway
Current Molecular Medicine 24, 1518 (2024); https://doi.org/10.2174/0115665240263859231018110107
/content/journals/cmm/10.2174/0115665240263859231018110107
/content/journals/cmm/10.2174/0115665240263859231018110107
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  • Article Type:     Research Article
Keyword(s): cGAS-STING pathway; dopaminergic neurons; ferroptosis; METTL14; mitochondrial dysfunction; parkinson's disease; TRAF6

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