{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:56:20Z","timestamp":1792788980494,"version":"4.5.0"},"reference-count":38,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T00:00:00Z","timestamp":1789862400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Natural Science Foundation of China","award":["82370837"],"award-info":[{"award-number":["82370837"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"crossref"}]},{"name":"National Natural Science Foundation of China","award":["82570859"],"award-info":[{"award-number":["82570859"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"crossref"}]},{"award":["82370837"],"award-info":[{"award-number":["82370837"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"award":["82570859"],"award-info":[{"award-number":["82570859"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Hyperglycemia-driven mitochondrial dysfunction is a primary driver of diabetic encephalopathy (DE). Here, we identify a novel nucleocytoplasmic \u201cdual effect\u201d of DISC1 that coordinates mitochondrial Ca2+ overload under high-glucose conditions. Using nucleocytoplasmic fractionation and mass spectrometry, we demonstrate that high glucose triggers PAK2-mediated phosphorylation of DISC1, necessitating its nuclear translocation. In the nucleus, DISC1 acts as a coactivator for the transcription factor RFX1 to induce Grp75, a critical tethering protein of the GRP75\/IP3R1\/VDAC1 complex that facilitates Ca2+ transfer from the endoplasmic reticulum to mitochondria. Conversely, we find that cytoplasmic DISC1 physically sequesters GRP75, hindering the assembly of the Ca2+ conduction complex. Enhanced nuclear translocation of DISC1 results in reduced cytoplasmic DISC1 levels. This depletion removes the \u201cmolecular brake\u201d on Ca2+ influx, synergizing with the nuclear signaling pathway to drive mitochondrial Ca2+ overload. Together, our findings suggest that high glucose hijacks DISC1 through a bipartite mechanism: the upregulation of Ca2+ conduction and the concurrent loss of cytoplasmic inhibition. Targeting DISC1 may represent a potential therapeutic strategy for mitigating neurodegeneration in DE.<\/jats:p>","DOI":"10.3390\/biom16091366","type":"journal-article","created":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T09:01:38Z","timestamp":1789981298000},"page":"1366","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["DISC1 Orchestrates Mitochondrial Calcium Overload in Diabetic Encephalopathy Through a Dual Nucleocytoplasmic Mechanism"],"prefix":"10.3390","volume":"16","author":[{"given":"Lu","family":"He","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China"},{"name":"Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"}]},{"given":"Hao","family":"Li","sequence":"additional","affiliation":[{"name":"Key Laboratory of Neurological Diseases of Hubei Province and National Education Ministry, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"}]},{"given":"Rui","family":"Yin","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, 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China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"}]},{"given":"Yong","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4041-0437","authenticated-orcid":false,"given":"Man","family":"Li","sequence":"additional","affiliation":[{"name":"Key Laboratory of Neurological Diseases of Hubei Province and National Education Ministry, School of Basic 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Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e02535","DOI":"10.1002\/advs.202502535","article-title":"Epigenetic regulation of dapk1 and netrin-1 drives diabetic encephalopathy","volume":"12","author":"Zhou","year":"2025","journal-title":"Adv. Sci."},{"key":"ref_3","unstructured":"GBD 2021 Nervous System Disorders Collaborators (2024). Global, regional, and national burden of disorders affecting the nervous system, 1990\u20132021: A systematic analysis for the Global burden of disease study 2021. Lancet Neurol., 23, 344\u2013381."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"102996","DOI":"10.1016\/j.redox.2023.102996","article-title":"Phosphatidate phosphatase Lipin1 involves in diabetic encephalopathy pathogenesis via regulating synaptic mitochondrial dynamics","volume":"69","author":"Han","year":"2024","journal-title":"Redox Biol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1186\/s12974-025-03441-3","article-title":"Phosphatidate phosphatase Lipin1 alters mitochondria-associated endoplasmic reticulum membranes (MAMs) homeostasis: Effects which contribute to the development of diabetic encephalopathy","volume":"22","author":"Huang","year":"2025","journal-title":"J. Neuroinflamm."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1899","DOI":"10.1016\/j.neuron.2022.03.015","article-title":"Programming axonal mitochondrial maintenance and bioenergetics in neurodegeneration and regeneration","volume":"110","author":"Cheng","year":"2022","journal-title":"Neuron"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"108170","DOI":"10.1016\/j.phrs.2026.108170","article-title":"Mitochondrial dysfunction as a driver of chronic pain: New insights and therapeutic prospects","volume":"227","author":"Fan","year":"2026","journal-title":"Pharmacol. Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1667","DOI":"10.1161\/CIRCULATIONAHA.124.072661","article-title":"FMO2 prevents pathological cardiac hypertrophy by maintaining the ER-mitochondria association through interaction with IP3R2-Grp75-VDAC1","volume":"151","author":"Xiao","year":"2025","journal-title":"Circulation"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"108177","DOI":"10.1016\/j.phrs.2026.108177","article-title":"SERCA2 dysfunction drives vascular calcification via coupling with TSPO-MCU at mitochondria-associated endoplasmic reticulum membranes","volume":"227","author":"Pi","year":"2026","journal-title":"Pharmacol. Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1913","DOI":"10.1161\/CIRCULATIONAHA.118.033552","article-title":"Hyperglycemia-driven inhibition of AMP-activated protein kinase \u03b12 induces diabetic cardiomyopathy by promoting mitochondria-associated endoplasmic reticulum membranes in vivo","volume":"139","author":"Wu","year":"2019","journal-title":"Circulation"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Wang, X., Li, S., Xiang, X., Zhang, X., Yu, C., Qing, D., Law, B.Y., and Tang, Y. (J. Adv. Res., 2026). Modulating GRP75 to restore calcium homeostasis: A novel neuroprotective strategy of CRSE6# in Parkinson\u2019s disease models, J. Adv. Res., in press.","DOI":"10.1016\/j.jare.2026.03.034"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1016\/j.freeradbiomed.2022.01.024","article-title":"T3-induced enhancement of mitochondrial Ca(2+) uptake as a boost for mitochondrial metabolism","volume":"181","author":"Tawfik","year":"2022","journal-title":"Free Radic. Biol. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1292","DOI":"10.1161\/CIRCRESAHA.123.323882","article-title":"Inhibition of the mPTP and lipid peroxidation is additively protective against I\/R injury","volume":"134","author":"Mendoza","year":"2024","journal-title":"Circ. Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"102289","DOI":"10.1016\/j.redox.2022.102289","article-title":"Ip3r1\/grp75\/vdac1 complex mediates endoplasmic reticulum stress-mitochondrial oxidative stress in diabetic atrial remodeling","volume":"52","author":"Yuan","year":"2022","journal-title":"Redox Biol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Norkett, R., Lesept, F., and Kittler, J.T. (2020). DISC1 Regulates mitochondrial trafficking in a Miro1-GTP-dependent manner. Front. Cell Dev. Biol., 8.","DOI":"10.3389\/fcell.2020.00449"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e12860","DOI":"10.1111\/acel.12860","article-title":"Disrupted-in-schizophrenia-1 protects synaptic plasticity in a transgenic mouse model of Alzheimer\u2019s disease as a mitophagy receptor","volume":"18","author":"Wang","year":"2019","journal-title":"Aging Cell"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"6810","DOI":"10.1038\/s41467-021-27114-w","article-title":"Developmental decrease of entorhinal-hippocampal communication in immune-challenged DISC1 knockdown mice","volume":"12","author":"Xu","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1186\/s12929-018-0473-x","article-title":"The TRAX, DISC1, and GSK3 complex in mental disorders and therapeutic interventions","volume":"25","author":"Weng","year":"2018","journal-title":"J. Biomed. Sci."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Shia, W.C., Ku, T.H., Tsao, Y.M., Hsia, C.H., Chang, Y.M., Huang, C.H., Chung, Y.C., Hsu, S.L., Liang, K.W., and Hsu, F.R. (2011). Genetic copy number variants in myocardial infarction patients with hyperlipidemia. BMC Genom., 12.","DOI":"10.1186\/1471-2164-12-S3-S23"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1186\/s12014-021-09320-2","article-title":"The plasma peptides of Alzheimer\u2019s disease","volume":"18","author":"Bowden","year":"2021","journal-title":"Clin. Proteom."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"854","DOI":"10.2337\/db20-0487","article-title":"Lifestyle intervention in pregnant women with obesity impacts cord blood DNA methylation, which associates with body composition in the offspring","volume":"70","author":"Jonsson","year":"2021","journal-title":"Diabetes"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2748","DOI":"10.1016\/j.celrep.2017.11.043","article-title":"DISC1 modulates neuronal stress responses by gate-keeping ER-mitochondria Ca(2+) transfer through the MAM","volume":"21","author":"Park","year":"2017","journal-title":"Cell Rep."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1016\/j.mcn.2005.08.021","article-title":"Disrupted in schizophrenia 1 (DISC1): Subcellular targeting and induction of ring mitochondria","volume":"30","author":"Millar","year":"2005","journal-title":"Mol. Cell Neurosci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1346","DOI":"10.1038\/s41380-019-0485-2","article-title":"Structural interaction between DISC1 and ATF4 underlying transcriptional and synaptic dysregulation in an iPSC model of mental disorders","volume":"26","author":"Wang","year":"2021","journal-title":"Mol. Psychiatry"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1002\/biof.1884","article-title":"DISC1 inhibits GSK3\u03b2 activity to prevent tau hyperphosphorylation under diabetic encephalopathy","volume":"49","author":"Chen","year":"2023","journal-title":"Biofactors"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1186\/s12933-024-02258-3","article-title":"Growth differentiation factor 11 regulates high glucose-induced cardiomyocyte pyroptosis and dia-betic cardiomyopathy by inhibiting inflammasome activation","volume":"23","author":"Zhang","year":"2024","journal-title":"Cardiovasc. Diabetol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1186\/s13578-021-00563-y","article-title":"ApoE4 (Delta272-299) induces mitochondrial-associated membrane formation and mitochondrial impairment by enhancing GRP75-modulated mitochondrial calcium overload in neuron","volume":"11","author":"Liang","year":"2021","journal-title":"Cell Biosci."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Hang, W., He, B., Chen, J., Xia, L., Wen, B., Liang, T., Wang, X., Zhang, Q., Wu, Y., and Chen, Q. (2018). Berberine ameliorates high glucose-induced cardiomyocyte injury via AMPK signaling activation to stimulate mitochondrial biogenesis and restore autophagic flux. Front. Pharmacol., 9.","DOI":"10.3389\/fphar.2018.01121"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1645","DOI":"10.1093\/eurheartj\/ehae911","article-title":"CCN5 suppresses injury-induced vascular restenosis by inhibiting smooth muscle cell proliferation and facilitating endothelial repair via thymosin \u03b24 and Cd9 pathway","volume":"46","author":"Zhang","year":"2025","journal-title":"Eur. Heart J."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"111751","DOI":"10.1016\/j.intimp.2024.111751","article-title":"RFX1 regulates foam cell formation and atherosclerosis by mediating CD36 expression","volume":"130","author":"Yang","year":"2024","journal-title":"Int. Immunopharmacol."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Ramos-Alvarez, I., and Jensen, R.T. (2025). The important role of p21-activated kinases in pancreatic exocrine function. Biology, 14.","DOI":"10.3390\/biology14020113"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Huang, Q.Y., Lai, X.N., Qian, X.L., Lv, L.C., Li, J., Duan, J., Xiao, X.H., and Xiong, L.X. (2019). Cdc42: A novel regulator of insulin secretion and diabetes-associated diseases. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20010179"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"898","DOI":"10.1038\/mp.2013.38","article-title":"DISC1-ATF4 transcriptional repression complex: Dual regulation of the cAMP-PDE4 cascade by DISC1","volume":"18","author":"Soda","year":"2013","journal-title":"Mol. Psychiatry"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"598","DOI":"10.1016\/j.tcb.2021.02.003","article-title":"Balancing ER-Mitochondrial Ca2+ fluxes in health and disease","volume":"31","author":"Loncke","year":"2021","journal-title":"Trends Cell Biol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1016\/j.tcb.2022.07.004","article-title":"Calcium homeostasis and cancer: Insights from endoplasmic reticulum-centered organelle communications","volume":"33","author":"Zheng","year":"2023","journal-title":"Trends Cell Biol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"700","DOI":"10.1124\/pr.110.003814","article-title":"Endoplasmic reticulum Ca2+ handling in excitable cells in health and disease","volume":"63","author":"Stutzmann","year":"2011","journal-title":"Pharmacol. Rev."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"eabq2424","DOI":"10.1126\/sciimmunol.abq2424","article-title":"Mitochondria-ER contact mediated by MFN2-SERCA2 interaction supports CD8+ T cell metabolic fitness and function in tumors","volume":"8","author":"Yang","year":"2023","journal-title":"Sci. Immunol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1161\/CIRCRESAHA.123.322686","article-title":"TMEM215 prevents endothelial cell apoptosis in vessel regression by blunting BIK-regulated ER-to-mitochondrial Ca influx","volume":"133","author":"Zhang","year":"2023","journal-title":"Circ. Res."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/16\/9\/1366\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T04:41:47Z","timestamp":1790052107000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/16\/9\/1366"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,20]]},"references-count":38,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["biom16091366"],"URL":"https:\/\/doi.org\/10.3390\/biom16091366","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,20]]}}}