{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T11:18:13Z","timestamp":1783423093915,"version":"3.54.6"},"reference-count":44,"publisher":"IMR Press","issue":"6","license":[{"start":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T00:00:00Z","timestamp":1780876800000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"project from major project of Sichuan provincial administration of traditional Chinese medicine","award":["2024ZD001"],"award-info":[{"award-number":["2024ZD001"]}]},{"name":"Luzhou science and technology bureau program","award":["2023SYF128"],"award-info":[{"award-number":["2023SYF128"]}]},{"name":"Luzhou science and technology bureau program","award":["2023JYJ056"],"award-info":[{"award-number":["2023JYJ056"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Front. Biosci. (Landmark Ed)"],"abstract":"<jats:p>Background:Clinical epidemiological data have shown that hypomagnesemia, defined as a serum Mg2+ concentration of &lt;0.7 mmol\/L, independently increases the risk of diabetic retinopathy (DR) in patients with type 2 diabetes mellitus (T2DM). The molecular and cellular mechanisms through which hypomagnesemia accelerates the onset and progression of DR remain largely undefined. The Transient Receptor Potential Cation Channel, Subfamily M, Member 7 (TRPM7) channel is expressed in the retina and is integral to the pathophysiological processes associated with hypomagnesemia. However, whether TRPM7 affects DR progression through its regulation of hypomagnesemia has not been established. M\u00fcller cells span the retina and are crucial for maintaining retinal homeostasis. Moreover, these cells significantly influence the onset and progression of DR. The current study assessed the impact of combined treatment with high-glucose (HG) and low-Mg2+ (LM) on retinal M\u00fcller cells, and also investigated the underlying molecular mechanism.Methods:M\u00fcller cells were treated with HG or HG combined with LM (HG\/LM). TRPM7-silenced M\u00fcller cells were generated by transduction with shRNA. Quantitative real-time PCR and Western blot analysis were performed to measure the levels of related genes and proteins, respectively. Cell viability, apoptosis, mitochondrial function, oxidative stress, and intracellular Ca2+ levels in M\u00fcller cells were analyzed using relevant assays.Results:Low Mg2+ was found to aggravate oxidative stress and mitochondrial dysfunction in M\u00fcller cells under HG stress, leading to decreased cell viability, increased apoptosis, and elevated expression of vascular endothelial growth factor. These effects were accompanied by the upregulation of TRPM7 and mitochondrial voltage-dependent anion channel 1 (VDAC1), as well as increased intracellular Ca2+ levels. Silencing of TRPM7 expression in M\u00fcller cells significantly decreased intracellular Ca2+, oxidative stress, mitochondrial dysfunction, and cell dysfunction under HG\/LM stress.Conclusions:Low Mg2+ exacerbates the dysfunction of M\u00fcller cells under HG stress via TRPM7\/Ca2+\/VDAC1 axis-mediated mitochondrial oxidative stress.<\/jats:p>","DOI":"10.31083\/fbl50306","type":"journal-article","created":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T10:50:51Z","timestamp":1783421451000},"source":"Crossref","is-referenced-by-count":0,"title":["TRPM7 Channel-Mediated Mitochondrial Oxidative Stress Induces Dysfunction of M\u00fcller Cells Under High Glucose and Low Mg2+ Stress"],"prefix":"10.31083","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7085-2098","authenticated-orcid":true,"given":"Ping","family":"Liu","sequence":"first","affiliation":[{"name":"Eye School of Chengdu University of TCM, \u200c611137 Chengdu, Sichuan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-5288-414X","authenticated-orcid":true,"given":"Zhen","family":"Guo","sequence":"additional","affiliation":[{"name":"School of Integrated Traditional and Western Medicine, Southwest Medical University, 646000 Luzhou, Sichuan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-2604-3715","authenticated-orcid":true,"given":"Jun","family":"Zhou","sequence":"additional","affiliation":[{"name":"School of Integrated Traditional and Western Medicine, Southwest Medical University, 646000 Luzhou, Sichuan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8594-8065","authenticated-orcid":true,"given":"Lin","family":"Mou","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, 646000 Luzhou, Sichuan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2243-9124","authenticated-orcid":true,"given":"Dongchuan","family":"Zuo","sequence":"additional","affiliation":[{"name":"Key Laboratory of Medical Electrophysiology, Southwest Medical University, \u200c646000\u200c Luzhou, Sichuan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8605-9756","authenticated-orcid":true,"given":"Junguo","family":"Duan","sequence":"additional","affiliation":[{"name":"Eye School of Chengdu University of TCM, \u200c611137 Chengdu, Sichuan, China"},{"name":"Eye Health With Traditional Chinese Medicine Key Laboratory of Sichuan Province, 610084 Chengdu, Sichuan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"16242","published-online":{"date-parts":[[2026,6,8]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","unstructured":"Singh A, Shadangi S, Gupta PK, Rana S. Type 2 Diabetes Mellitus: A Comprehensive Review of Pathophysiology, Comorbidities, and Emerging Therapies. Comprehensive Physiology. 2025; 15: e70003.","DOI":"10.1002\/cph4.70003"},{"key":"ref2","doi-asserted-by":"publisher","unstructured":"McNair P, Christiansen C, Madsbad S, Lauritzen E, Faber O, Binder C, et al. Hypomagnesemia, a risk factor in diabetic retinopathy. Diabetes. 1978; 27: 1075\u20131077.","DOI":"10.2337\/diab.27.11.1075"},{"key":"ref3","doi-asserted-by":"publisher","unstructured":"Pham PCT, Pham PMT, Pham SV, Miller JM, Pham PTT. Hypomagnesemia in patients with type 2 diabetes. Clinical Journal of the American Society of Nephrology: CJASN. 2007; 2: 366\u2013373.","DOI":"10.2215\/CJN.02960906"},{"key":"ref4","doi-asserted-by":"publisher","unstructured":"Oost LJ, van Heck JIP, Tack CJ, de Baaij JHF. The association between hypomagnesemia and poor glycaemic control in type 1 diabetes is limited to insulin resistant individuals. Scientific Reports. 2022; 12: 6433.","DOI":"10.1038\/s41598-022-10436-0"},{"key":"ref5","doi-asserted-by":"publisher","unstructured":"Oost LJ, Tack CJ, de Baaij JHF. Hypomagnesemia and Cardiovascular Risk in Type 2 Diabetes. Endocrine Reviews. 2023; 44: 357\u2013378.","DOI":"10.1210\/endrev\/bnac028"},{"key":"ref6","doi-asserted-by":"publisher","unstructured":"Gommers LMM, Hoenderop JGJ, Bindels RJM, de Baaij JHF. Hypomagnesemia in Type 2 Diabetes: A Vicious Circle? Diabetes. 2016; 65: 3\u201313.","DOI":"10.2337\/db15-1028"},{"key":"ref7","doi-asserted-by":"publisher","unstructured":"Brookfield KF, Mbata O. Magnesium Sulfate Use in Pregnancy for Preeclampsia Prophylaxis and Fetal Neuroprotection: Regimens in High-Income and Low\/Middle-Income Countries. Obstetrics and Gynecology Clinics of North America. 2023; 50: 89\u201399.","DOI":"10.1016\/j.ogc.2022.10.003"},{"key":"ref8","doi-asserted-by":"publisher","unstructured":"Topf JM, Murray PT. Hypomagnesemia and hypermagnesemia. Reviews in Endocrine & Metabolic Disorders. 2003; 4: 195\u2013206.","DOI":"10.1023\/a:1022950321817"},{"key":"ref9","doi-asserted-by":"publisher","unstructured":"\u00c7i\u011f E, Yard\u0131mc\u0131 M, \u00c7\u0131nar R, Y\u0131ld\u0131zhan K. Protective role of zingerone against high glucose-Induced retinal pigment epithelial cell damage through modulation of the TRPM2 channel pathway. Molecular Biology Reports. 2026; 53: 309.","DOI":"10.1007\/s11033-026-11476-9"},{"key":"ref10","doi-asserted-by":"publisher","unstructured":"Hamdan HZ, Nasser NM, Adam AM, Saleem MA, Elamin MI. Serum magnesium, iron and ferritin levels in patients with diabetic retinopathy attending Makkah Eye Complex, Khartoum, Sudan. Biological Trace Element Research. 2015; 165: 30\u201334.","DOI":"10.1007\/s12011-015-0236-4"},{"key":"ref11","doi-asserted-by":"publisher","unstructured":"Hatwal A, Gujral AS, Bhatia RP, Agrawal JK, Bajpai HS. Association of hypomagnesemia with diabetic retinopathy. Acta Ophthalmologica. 1989; 67: 714\u2013716.","DOI":"10.1111\/j.1755-3768.1989.tb04407.x"},{"key":"ref12","doi-asserted-by":"publisher","unstructured":"Gilliam JC, Wensel TG. TRP channel gene expression in the mouse retina. Vision Research. 2011; 51: 2440\u20132452.","DOI":"10.1016\/j.visres.2011.10.009"},{"key":"ref13","doi-asserted-by":"publisher","unstructured":"Ryazanova LV, Hu Z, Suzuki S, Chubanov V, Fleig A, Ryazanov AG. Elucidating the role of the TRPM7 alpha-kinase: TRPM7 kinase inactivation leads to magnesium deprivation resistance phenotype in mice. Scientific Reports. 2014; 4: 7599.","DOI":"10.1038\/srep07599"},{"key":"ref14","doi-asserted-by":"publisher","unstructured":"Liu M, Liu H, Kang GJ, Hartweck LM, Feng F, Kim E, et al. Cardiac TRPM7 Causes Diabetic Heart Failure With Preserved Ejection Fraction. JACC. Basic to Translational Science. 2025; 10: 101321.","DOI":"10.1016\/j.jacbts.2025.101321"},{"key":"ref15","doi-asserted-by":"publisher","unstructured":"Mart\u00ednez-Gil N, Kutsyr O, Fern\u00e1ndez-S\u00e1nchez L, S\u00e1nchez-S\u00e1ez X, Albertos-Arranz H, S\u00e1nchez-Castillo C, et al. Ischemia-Reperfusion Increases TRPM7 Expression in Mouse Retinas. International Journal of Molecular Sciences. 2023; 24: 16068.","DOI":"10.3390\/ijms242216068"},{"key":"ref16","doi-asserted-by":"publisher","unstructured":"Hu L, Xu G. Potential Protective Role of TRPM7 and Involvement of PKC\/ERK Pathway in Blue Light-Induced Apoptosis in Retinal Pigment Epithelium Cells in Vitro. Asia-Pacific Journal of Ophthalmology (Philadelphia, Pa.). 2021; 10: 572\u2013578.","DOI":"10.1097\/APO.0000000000000447"},{"key":"ref17","doi-asserted-by":"publisher","unstructured":"Ara\u00fajo RS, Santos DF, Silva GA. The role of the retinal pigment epithelium and M\u00fcller cells secretome in neovascular retinal pathologies. Biochimie. 2018; 155: 104\u2013108.","DOI":"10.1016\/j.biochi.2018.06.019"},{"key":"ref18","doi-asserted-by":"publisher","unstructured":"Subirada PV, Paz MC, Ridano ME, Lorenc VE, Vaglienti MV, Barcelona PF, et al. A journey into the retina: M\u00fcller glia commanding survival and death. The European Journal of Neuroscience. 2018; 47: 1429\u20131443.","DOI":"10.1111\/ejn.13965"},{"key":"ref19","doi-asserted-by":"publisher","unstructured":"Zhu L, Shen W, Lyons B, Wang Y, Zhou F, Gillies MC. Dysregulation of inter-photoreceptor retinoid-binding protein (IRBP) after induced M\u00fcller cell disruption. Journal of Neurochemistry. 2015; 133: 909\u2013918.","DOI":"10.1111\/jnc.13075"},{"key":"ref20","unstructured":"Rungger-Br\u00e4ndle E, Dosso AA, Leuenberger PM. Glial reactivity, an early feature of diabetic retinopathy. Investigative Ophthalmology & Visual Science. 2000; 41: 1971\u20131980."},{"key":"ref21","unstructured":"Li Q, Puro DG. Diabetes-induced dysfunction of the glutamate transporter in retinal M\u00fcller cells. Investigative Ophthalmology & Visual Science. 2002; 43: 3109\u20133116."},{"key":"ref22","doi-asserted-by":"publisher","unstructured":"Mu H, Zhang XM, Liu JJ, Dong L, Feng ZL. Effect of high glucose concentration on VEGF and PEDF expression in cultured retinal M\u00fcller cells. Molecular Biology Reports. 2009; 36: 2147\u20132151.","DOI":"10.1007\/s11033-008-9428-8"},{"key":"ref23","doi-asserted-by":"publisher","unstructured":"Xie B, Jiao Q, Cheng Y, Zhong Y, Shen X. Effect of pigment epithelium-derived factor on glutamate uptake in retinal Muller cells under high-glucose conditions. Investigative Ophthalmology & Visual Science. 2012; 53: 1023\u20131032.","DOI":"10.1167\/iovs.11-8695"},{"key":"ref24","doi-asserted-by":"publisher","unstructured":"Eastlake K, Banerjee PJ, Angbohang A, Charteris DG, Khaw PT, Limb GA. M\u00fcller glia as an important source of cytokines and inflammatory factors present in the gliotic retina during proliferative vitreoretinopathy. Glia. 2016; 64: 495\u2013506.","DOI":"10.1002\/glia.22942"},{"key":"ref25","doi-asserted-by":"publisher","unstructured":"Wang Y, Yu H, Li J, Liu W, Yu S, Lv P, et al. Th22 cells induce M\u00fcller cell activation via the Act1\/TRAF6 pathway in diabetic retinopathy. Cell and Tissue Research. 2022; 390: 367\u2013383.","DOI":"10.1007\/s00441-022-03689-8"},{"key":"ref26","doi-asserted-by":"publisher","unstructured":"Li X, Li B, Feng D, Hu H, Tang B, Yang J, et al. Upregulation of SQSTM1 Regulates Ferroptosis and Oxidative Stress in M\u00fcller Cells of the Diabetic Neural Retina by Modulating ACSL4. Journal of Diabetes Research. 2025; 2025: 1924668.","DOI":"10.1155\/jdr\/1924668"},{"key":"ref27","doi-asserted-by":"publisher","unstructured":"Tundo GR, Atzori MG, Boccaccini A, Cavaterra D, Bocedi A, Graziani G, et al. High-glucose stimulation triggers early transcription of a panel of proinflammatory mediators in rat Muller glia cells and retina primary explants. Acta Diabetologica. 2025; 62: 2121\u20132127.","DOI":"10.1007\/s00592-025-02543-x"},{"key":"ref28","doi-asserted-by":"publisher","unstructured":"Onuma S, Manabe A, Yoshino Y, Matsunaga T, Asai T, Ikari A. Upregulation of Chemoresistance by Mg2+ Deficiency through Elevation of ATP Binding Cassette Subfamily B Member 1 Expression in Human Lung Adenocarcinoma A549 Cells. Cells. 2021; 10: 1179.","DOI":"10.3390\/cells10051179"},{"key":"ref29","doi-asserted-by":"publisher","unstructured":"Barreto-Chang OL, Dolmetsch RE. Calcium imaging of cortical neurons using Fura-2 AM. Journal of Visualized Experiments : JoVE. 2009; 1067.","DOI":"10.3791\/1067"},{"key":"ref30","doi-asserted-by":"publisher","unstructured":"Liu M, Dudley SC. Magnesium, Oxidative Stress, Inflammation, and Cardiovascular Disease. Antioxidants (Basel, Switzerland). 2020; 9: 907.","DOI":"10.3390\/antiox9100907"},{"key":"ref31","doi-asserted-by":"publisher","unstructured":"He W, Tang P, Lv H. Targeting oxidative stress in diabetic retinopathy: mechanisms, pathology, and novel treatment approaches. Frontiers in Immunology. 2025; 16: 1571576.","DOI":"10.3389\/fimmu.2025.1571576"},{"key":"ref32","doi-asserted-by":"publisher","unstructured":"Nu\u00f1ez-Villena F, Becerra A, Echeverr\u00eda C, Brice\u00f1o N, Porras O, Armis\u00e9n R, et al. Increased expression of the transient receptor potential melastatin 7 channel is critically involved in lipopolysaccharide-induced reactive oxygen species-mediated neuronal death. Antioxidants & Redox Signaling. 2011; 15: 2425\u20132438.","DOI":"10.1089\/ars.2010.3825"},{"key":"ref33","doi-asserted-by":"publisher","unstructured":"Aarts M, Iihara K, Wei WL, Xiong ZG, Arundine M, Cerwinski W, et al. A key role for TRPM7 channels in anoxic neuronal death. Cell. 2003; 115: 863\u2013877.","DOI":"10.1016\/s0092-8674(03)01017-1"},{"key":"ref34","doi-asserted-by":"publisher","unstructured":"Weisthal S, Keinan N, Ben-Hail D, Arif T, Shoshan-Barmatz V. Ca(2+)-mediated regulation of VDAC1 expression levels is associated with cell death induction. Biochimica et Biophysica Acta. 2014; 1843: 2270\u20132281.","DOI":"10.1016\/j.bbamcr.2014.03.021"},{"key":"ref35","doi-asserted-by":"publisher","unstructured":"Li Y, Zhu L, Cai MX, Wang ZL, Zhuang M, Tan CY, et al. TGR5 supresses cGAS\/STING pathway by inhibiting GRP75-mediated endoplasmic reticulum-mitochondrial coupling in diabetic retinopathy. Cell Death & Disease. 2023; 14: 583.","DOI":"10.1038\/s41419-023-06111-5"},{"key":"ref36","doi-asserted-by":"publisher","unstructured":"Tien T, Zhang J, Muto T, Kim D, Sarthy VP, Roy S. High Glucose Induces Mitochondrial Dysfunction in Retinal M\u00fcller Cells: Implications for Diabetic Retinopathy. Investigative Ophthalmology & Visual Science. 2017; 58: 2915\u20132921.","DOI":"10.1167\/iovs.16-21355"},{"key":"ref37","doi-asserted-by":"publisher","unstructured":"Fujita K, Shindo Y, Katsuta Y, Goto M, Hotta K, Oka K. Intracellular Mg2+ protects mitochondria from oxidative stress in human keratinocytes. Communications Biology. 2023; 6: 868.","DOI":"10.1038\/s42003-023-05247-6"},{"key":"ref38","doi-asserted-by":"publisher","unstructured":"Kaliaperumal R, Venkatachalam R, Nagarajan P, Sabapathy SK. Association of Serum Magnesium with Oxidative Stress in the Pathogenesis of Diabetic Cataract. Biological Trace Element Research. 2021; 199: 2869\u20132873.","DOI":"10.1007\/s12011-020-02429-9"},{"key":"ref39","doi-asserted-by":"publisher","unstructured":"Wei C, Wang X, Chen M, Ouyang K, Song LS, Cheng H. Calcium flickers steer cell migration. Nature. 2009; 457: 901\u2013905.","DOI":"10.1038\/nature07577"},{"key":"ref40","doi-asserted-by":"publisher","unstructured":"Clark K, Langeslag M, van Leeuwen B, Ran L, Ryazanov AG, Figdor CG, et al. TRPM7, a novel regulator of actomyosin contractility and cell adhesion. The EMBO Journal. 2006; 25: 290\u2013301.","DOI":"10.1038\/sj.emboj.7600931"},{"key":"ref41","doi-asserted-by":"publisher","unstructured":"Du J, Xie J, Zhang Z, Tsujikawa H, Fusco D, Silverman D, et al. TRPM7-mediated Ca2+ signals confer fibrogenesis in human atrial fibrillation. Circulation Research. 2010; 106: 992\u20131003.","DOI":"10.1161\/CIRCRESAHA.109.206771"},{"key":"ref42","doi-asserted-by":"publisher","unstructured":"Liu M, Liu H, Feng F, Krook-Magnuson E, Dudley SC. TRPM7 kinase mediates hypomagnesemia-induced seizure-related death. Scientific Reports. 2023; 13: 7855.","DOI":"10.1038\/s41598-023-34789-2"},{"key":"ref43","doi-asserted-by":"publisher","unstructured":"Hu H, Nie D, Fang M, He W, Zhang J, Liu X, et al. M\u00fcller cells under hydrostatic pressure modulate retinal cell survival via TRPV1\/PLC\u03b31 complex-mediated calcium influx in experimental glaucoma. The FEBS Journal. 2024; 291: 2703\u20132714.","DOI":"10.1111\/febs.17075"},{"key":"ref44","doi-asserted-by":"publisher","unstructured":"Li Q, Cheng Y, Zhang S, Sun X, Wu J. TRPV4-induced M\u00fcller cell gliosis and TNF-\u03b1 elevation-mediated retinal ganglion cell apoptosis in glaucomatous rats via JAK2\/STAT3\/NF-\u03baB pathway. Journal of Neuroinflammation. 2021; 18: 271.","DOI":"10.1186\/s12974-021-02315-8"}],"container-title":["Frontiers in Bioscience-Landmark"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.imrpress.com\/journal\/FBL\/31\/6\/10.31083\/FBL50306","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T10:54:07Z","timestamp":1783421647000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.imrpress.com\/journal\/FBL\/31\/6\/10.31083\/FBL50306"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,8]]},"references-count":44,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2026]]}},"alternative-id":["S2768-6701(26)02101-5"],"URL":"https:\/\/doi.org\/10.31083\/fbl50306","relation":{},"ISSN":["2768-6701","2768-6698"],"issn-type":[{"value":"2768-6701","type":"print"},{"value":"2768-6698","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,8]]},"article-number":"50306"}}