{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T06:03:50Z","timestamp":1789625030219,"version":"build-2803163510"},"reference-count":56,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T00:00:00Z","timestamp":1789603200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005145","name":"Basic Research Program of Jiangsu Province","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100005145","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell Dev. Biol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Enamel hypomineralization is a prevalent developmental dental defect associated with several early-life risk factors, including hyperthermia. However, the cellular mechanisms linking hyperthermia to impaired enamel mineralization remain unclear. This study investigated the potential role of transient receptor potential vanilloid 1 (TRPV1) in hyperthermia-associated ameloblast dysfunction.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Using a mouse ameloblast-lineage cell (ALC) model, we performed quantitative real-time PCR (qRT\u2010PCR), alkaline phosphatase (ALP) staining, Alizarin Red S (ARS) staining, RNA sequencing, immunohistochemistry, Western blotting, molecular intervention experiments, intracellular and mitochondrial calcium imaging, reactive oxygen species measurements, and mitochondrial functional assays.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      RNA sequencing and immunohistochemistry identified TRPV1 as a candidate heat-responsive channel expressed in ameloblasts. Hyperthermia was associated with reduced mineralization-related markers, increased intracellular and mitochondrial Ca\n                      <jats:sup>2+<\/jats:sup>\n                      signals and reactive oxygen species levels, decreased mitochondrial membrane potential, and impaired ATP content and NAD\n                      <jats:sup>+<\/jats:sup>\n                      \/NADH ratio. Pharmacological inhibition and genetic suppression of TRPV1 partially alleviated these hyperthermia-associated alterations.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>These findings support the involvement of TRPV1 in hyperthermia\u2010associated calcium dysregulation, mitochondrial dysfunction, and impaired mineralization-related responses in cultured ALCs. The results provide a testable framework for further in vivo investigation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fcell.2026.1903038","type":"journal-article","created":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T05:33:01Z","timestamp":1789623181000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["TRPV1 mediates mitochondrial dysfunction in hyperthermia\u2013induced ameloblast mineralization defects"],"prefix":"10.3389","volume":"14","author":[{"given":"Jingyi","family":"Li","sequence":"first","affiliation":[{"name":"Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Institute of Stomatology, Nanjing University","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Fu","sequence":"additional","affiliation":[{"name":"Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Institute of Stomatology, Nanjing University","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiwen","family":"Pan","sequence":"additional","affiliation":[{"name":"Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Institute of Stomatology, Nanjing University","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huiwen","family":"Zheng","sequence":"additional","affiliation":[{"name":"Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Institute of Stomatology, Nanjing University","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianghui","family":"Xing","sequence":"additional","affiliation":[{"name":"Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Institute of Stomatology, Nanjing University","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,17]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"S413","DOI":"10.3233\/JAD\u20132010\u2013100465","article-title":"Calcium and mitochondrial reactive oxygen species generation: how to read the facts","volume":"20","author":"Adam\u2013Vizi","year":"2010","journal-title":"J. Alzheimers Dis."},{"key":"B2","doi-asserted-by":"publisher","first-page":"102615","DOI":"10.1016\/j.jtherbio.2020.102615","article-title":"Hyperthermia and protein homeostasis: cytoprotection and cell death","volume":"91","author":"Ahmed","year":"2020","journal-title":"J. Therm. Biol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"9329492","DOI":"10.1155\/ijod\/9329492","article-title":"Navigating the complexities of molar incisor hypomineralization: challenges and strategies in pediatric dentistry","volume":"2025","author":"Al\u2013Nerabieah","year":"2025","journal-title":"Int. J. Dent."},{"key":"B4","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1007\/s00784\u2013025\u201306411\u20134","article-title":"Epidemiological trends in enamel hypomineralisation and molar\u2013incisor hypomineralisation: a systematic review and meta\u2013analysis","volume":"29","author":"Ammar","year":"2025","journal-title":"Clin. Oral Investig."},{"key":"B5","doi-asserted-by":"publisher","first-page":"1062042","DOI":"10.3389\/fphys.2022.1062042","article-title":"Energy metabolic shift contributes to the phenotype modulation of maturation stage ameloblasts","volume":"13","author":"Arai","year":"2022","journal-title":"Front. Physiol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"6135","DOI":"10.3390\/ijms22116135","article-title":"TRPV1: role in skin and skin diseases and potential target for improving wound healing","volume":"22","author":"Bagood","year":"2021","journal-title":"Int. J. Mol. Sci."},{"key":"B7","doi-asserted-by":"publisher","first-page":"81","DOI":"10.3390\/children4090081","article-title":"Fever in children: pearls and pitfalls","volume":"4","author":"Barbi","year":"2017","journal-title":"Child. (Basel)"},{"key":"B8","doi-asserted-by":"publisher","first-page":"3421","DOI":"10.3390\/ijms21103421","article-title":"TRPV1: structure, endogenous agonists, and mechanisms","volume":"21","author":"Ben\u00edtez\u2013Angeles","year":"2020","journal-title":"Int. J. Mol. Sci."},{"key":"B9","doi-asserted-by":"publisher","first-page":"817","DOI":"10.1152\/ajpcell.00139.2004","article-title":"Calcium, ATP, and ROS: a mitochondrial love\u2013hate triangle","volume":"287","author":"Brookes","year":"2004","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"816","DOI":"10.1038\/39807","article-title":"The capsaicin receptor: a heat\u2013activated ion channel in the pain pathway","volume":"389","author":"Caterina","year":"1997","journal-title":"Nature"},{"key":"B11","doi-asserted-by":"publisher","first-page":"538","DOI":"10.3389\/fphys.2020.00538","article-title":"Mitochondrial function in Enamel Development","volume":"11","author":"Costiniti","year":"2020","journal-title":"Front. Physiol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"730913","DOI":"10.3389\/fendo.2021.730913","article-title":"Calcium transport in Specialized dental Epithelia and its modulation by fluoride","volume":"12","author":"Costiniti","year":"2021","journal-title":"Front. Endocrinol. (Lausanne)"},{"key":"B13","doi-asserted-by":"publisher","first-page":"e22169","DOI":"10.1096\/fj.202100602R","article-title":"Mitochondria modulate ameloblast Ca2+ signaling","volume":"36","author":"Costiniti","year":"2022","journal-title":"FASEB J."},{"key":"B14","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1111\/j.1365\u2013263X.2008.00966.x","article-title":"Aetiology of molar\u2013incisor hypomineralization: a critical review","volume":"19","author":"Crombie","year":"2009","journal-title":"Int. J. Paediatr. Dent."},{"key":"B15","doi-asserted-by":"publisher","first-page":"2211","DOI":"10.1042\/BST20210301","article-title":"Thermodynamic and structural basis of temperature\u2013dependent gating in TRP channels","volume":"49","author":"Diaz\u2013Franulic","year":"2021","journal-title":"Biochem. Soc. Trans."},{"key":"B16","doi-asserted-by":"publisher","first-page":"1336416","DOI":"10.3389\/fmolb.2023.1336416","article-title":"Neither too much nor too little: mitochondrial calcium concentration as a balance between physiological and pathological conditions","volume":"10","author":"D\u2019Angelo","year":"2023","journal-title":"Front. Mol. Biosci."},{"key":"B17","doi-asserted-by":"publisher","first-page":"1778","DOI":"10.1016\/j.bbamcr.2018.04.013","article-title":"Altered Ca2+ signaling in enamelopathies","volume":"1865","author":"Eckstein","year":"2018","journal-title":"Biochim. Biophys. Acta Mol. Cell Res."},{"key":"B18","doi-asserted-by":"publisher","first-page":"eaav4663","DOI":"10.1126\/scisignal.aav4663","article-title":"Differential regulation of Ca2+ influx by ORAI channels mediates enamel mineralization","volume":"12","author":"Eckstein","year":"2019","journal-title":"Sci. Signal"},{"key":"B19","doi-asserted-by":"publisher","first-page":"1400118","DOI":"10.3389\/fnmol.2024.1400118","article-title":"The dual role of TRPV1 in peripheral neuropathic pain: pain switches caused by its sensitization or desensitization","volume":"17","author":"Gao","year":"2024","journal-title":"Front. Mol. Neurosci."},{"key":"B20","doi-asserted-by":"publisher","first-page":"1435","DOI":"10.1523\/JNEUROSCI.5150\u201309.2010","article-title":"Contributions of different modes of TRPV1 activation to TRPV1 antagonist\u2013induced hyperthermia","volume":"30","author":"Garami","year":"2010","journal-title":"J. Neurosci."},{"key":"B21","doi-asserted-by":"publisher","first-page":"128","DOI":"10.1124\/jpet.107.125674","article-title":"Repeated administration of vanilloid receptor TRPV1 antagonists attenuates hyperthermia elicited by TRPV1 blockade","volume":"323","author":"Gavva","year":"2007","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"B22","doi-asserted-by":"publisher","first-page":"713","DOI":"10.1038\/s41580\u2013018\u20130052\u20138","article-title":"The machineries, regulation and cellular functions of mitochondrial calcium","volume":"19","author":"Giorgi","year":"2018","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"42385","DOI":"10.1038\/srep42385","article-title":"TRPV1 deletion impaired fracture healing and inhibited osteoclast and osteoblast differentiation","volume":"7","author":"He","year":"2017","journal-title":"Sci. Rep."},{"key":"B24","doi-asserted-by":"publisher","first-page":"1312","DOI":"10.21037\/atm\u201320\u20136309","article-title":"Diosmetin reduces bone loss and osteoclastogenesis by regulating the expression of TRPV1 in osteoporosis rats","volume":"8","author":"Hu","year":"2020","journal-title":"Ann. Transl. Med."},{"key":"B25","doi-asserted-by":"publisher","first-page":"100667","DOI":"10.1016\/j.job.2025.100667","article-title":"Role of glucose metabolism in amelogenesis","volume":"67","author":"Ida\u2013Yonemochi","year":"2025","journal-title":"J. Oral Biosci."},{"key":"B26","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1007\/BF03262714","article-title":"Prevalence and diagnosis of molar\u2013incisor\u2013hypomineralisation (MIH): a systematic review","volume":"11","author":"J\u00e4levik","year":"2010","journal-title":"Eur. Arch. Paediatr. Dent."},{"key":"B27","doi-asserted-by":"publisher","first-page":"100650","DOI":"10.1016\/j.ijmmb.2024.100650","article-title":"Approach to fever in children","volume":"50","author":"Jayashree","year":"2024","journal-title":"Indian J. Med. Microbiol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"8882","DOI":"10.3390\/ijms21238882","article-title":"TRPV1 channel: a noxious signal transducer that affects mitochondrial function","volume":"21","author":"Ju\u00e1rez\u2013Contreras","year":"2020","journal-title":"Int. J. Mol. Sci."},{"key":"B29","doi-asserted-by":"publisher","first-page":"111","DOI":"10.3390\/dj11050111","article-title":"Etiological factors of molar incisor hypomineralization: a systematic review and meta\u2013analysis","volume":"11","author":"Ju\u00e1rez\u2013L\u00f3pez","year":"2023","journal-title":"Dent. J. (Basel)"},{"key":"B30","doi-asserted-by":"publisher","first-page":"785","DOI":"10.1007\/s00775\u2013024\u201302078\u20136","article-title":"Rapid method for screening of both calcium and magnesium chelation with comparison of 21 known metal chelators","volume":"29","author":"Kone\u010dn\u00fd","year":"2024","journal-title":"J. Biol. Inorg. Chem."},{"key":"B31","doi-asserted-by":"publisher","first-page":"1776","DOI":"10.1002\/jcp.22911","article-title":"Requirements for ion and solute transport, and pH regulation during enamel maturation","volume":"227","author":"Lacruz","year":"2012","journal-title":"J. Cell Physiol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"939","DOI":"10.1152\/physrev.00030.2016","article-title":"Dental enamel formation and implications for oral health and disease","volume":"97","author":"Lacruz","year":"2017","journal-title":"Physiol. Rev."},{"key":"B33","doi-asserted-by":"publisher","first-page":"17922","DOI":"10.1038\/s41598\u2013021\u201395875\u2013x","article-title":"Hypersensitivity in teeth affected by molar\u2013incisor hypomineralization (MIH)","volume":"11","author":"Linner","year":"2021","journal-title":"Sci. Rep."},{"key":"B34","doi-asserted-by":"publisher","first-page":"340","DOI":"10.1111\/eos.12619","article-title":"Molecular insights into hypomineralized enamel","volume":"127","author":"Malmberg","year":"2019","journal-title":"Eur. J. Oral Sci."},{"key":"B35","doi-asserted-by":"publisher","first-page":"6209","DOI":"10.3390\/ijms26136209","article-title":"The morphogenesis, pathogenesis, and molecular regulation of human tooth development\u2014A histological review","volume":"26","author":"Novacescu","year":"2025","journal-title":"Int. J. Mol. Sci."},{"key":"B36","doi-asserted-by":"publisher","first-page":"15803","DOI":"10.1038\/srep15803","article-title":"Dental enamel cells express functional SOCE channels","volume":"5","author":"Nurbaeva","year":"2015","journal-title":"Sci. Rep."},{"key":"B37","doi-asserted-by":"publisher","first-page":"801","DOI":"10.3389\/fphys.2018.00801","article-title":"Evidence that calcium entry into calcium\u2013transporting dental enamel cells is regulated by cholecystokinin, acetylcholine and ATP","volume":"9","author":"Nurbaeva","year":"2018","journal-title":"Front. Physiol."},{"key":"B38","doi-asserted-by":"publisher","first-page":"4999","DOI":"10.1172\/JCI136621","article-title":"12(S)\u2013HETE mediates diabetes\u2013induced endothelial dysfunction by activating intracellular endothelial cell TRPV1","volume":"130","author":"Otto","year":"2020","journal-title":"J. Clin. Invest."},{"key":"B39","doi-asserted-by":"publisher","first-page":"184","DOI":"10.1007\/BF03262594","article-title":"Pulpal expression of TRPV1 in molar incisor hypomineralisation","volume":"8","author":"Rodd","year":"2007","journal-title":"Eur. Arch. Paediatr. Dent."},{"key":"B40","doi-asserted-by":"publisher","first-page":"400","DOI":"10.1016\/j.archoralbio.2014.01.005","article-title":"The effect of high temperature on the development of mouse dental enamel in vitro","volume":"59","author":"Ryyn\u00e4nen","year":"2014","journal-title":"Arch. Oral Biol."},{"key":"B41","doi-asserted-by":"publisher","first-page":"1024","DOI":"10.1177\/0022034510375829","article-title":"Regulation of dental enamel shape and hardness","volume":"89","author":"Simmer","year":"2010","journal-title":"J. Dent. Res."},{"key":"B42","doi-asserted-by":"publisher","first-page":"435","DOI":"10.3389\/fphys.2017.00435","article-title":"Amelogenesis imperfecta; genes, proteins, and pathways","volume":"8","author":"Smith","year":"2017","journal-title":"Front. Physiol."},{"key":"B43","doi-asserted-by":"publisher","first-page":"2071","DOI":"10.3390\/app11052071","article-title":"Modeling the effects of calcium overload on mitochondrial ultrastructural remodeling","volume":"11","author":"Strubbe\u2013Rivera","year":"2021","journal-title":"Appl. Sci. (Basel)."},{"key":"B44","doi-asserted-by":"publisher","first-page":"18362","DOI":"10.3390\/ijms151018362","article-title":"TRPV1 Activation Exacerbates Hypoxia\/Reoxygenation\u2013Induced Apoptosis in H9C2 Cells via Calcium Overload and Mitochondrial Dysfunction","volume":"15","author":"Sun","year":"2014","journal-title":"Int. J. Mol. Sci."},{"key":"B45","doi-asserted-by":"publisher","first-page":"331","DOI":"10.1111\/ipd.13129","article-title":"Influence of genetics on the occurrence of enamel hypomineralization affecting permanent and primary teeth: a scoping review","volume":"34","author":"Teixeira","year":"2024","journal-title":"Int. J. Paediatr. Dent."},{"key":"B46","doi-asserted-by":"publisher","first-page":"2322","DOI":"10.3390\/cells12182322","article-title":"TRPV1 channels are new players in the Reticulum\u2013Mitochondria Ca2+ coupling in a rat cardiomyoblast cell line","volume":"12","author":"Tessier","year":"2023","journal-title":"Cells"},{"key":"B47","doi-asserted-by":"publisher","first-page":"100009","DOI":"10.1016\/j.jphyss.2025.100009","article-title":"TRPV1 and thermosensitivity","volume":"75","author":"Tominaga","year":"2025","journal-title":"J. Physiol. Sci."},{"key":"B48","doi-asserted-by":"publisher","first-page":"531","DOI":"10.1016\/S0896\u20136273(00)80564\u20134","article-title":"The cloned Capsaicin receptor integrates multiple pain\u2013producing stimuli","volume":"21","author":"Tominaga","year":"1998","journal-title":"Neuron"},{"key":"B49","doi-asserted-by":"publisher","first-page":"464","DOI":"10.1016\/j.archoralbio.2005.12.001","article-title":"Effect of turpentine\u2013induced fever during the enamel formation of rat incisor","volume":"51","author":"Tung","year":"2006","journal-title":"Arch. Oral Biol."},{"key":"B50","doi-asserted-by":"publisher","first-page":"1891","DOI":"10.3390\/biom12121891","article-title":"Calcium overload and mitochondrial metabolism","volume":"12","author":"Walkon","year":"2022","journal-title":"Biomolecules"},{"key":"B51","doi-asserted-by":"publisher","first-page":"94S","DOI":"10.1177\/0022034514527971","article-title":"STIM1 and SLC24A4 are critical for enamel maturation","volume":"93","author":"Wang","year":"2014","journal-title":"J. Dent. Res."},{"key":"B52","first-page":"110","article-title":"Judgement criteria for molar incisor hypomineralisation (MIH) in epidemiologic studies: a summary of the European meeting on MIH held in Athens, 2003","volume":"4","author":"Weerheijm","year":"2003","journal-title":"Eur. J. Paediatr. Dent."},{"key":"B53","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1111\/j.1365\u2013263X.2007.00901.x","article-title":"Molar incisor hypomineralization: a study of aetiological factors in a group of UK children","volume":"18","author":"Whatling","year":"2008","journal-title":"Int. J. Paediatr. Dent."},{"key":"B54","doi-asserted-by":"publisher","first-page":"109733","DOI":"10.1016\/j.cellsig.2020.109733","article-title":"Capsaicin induces mitochondrial dysfunction and apoptosis in Anaplastic thyroid carcinoma cells via TRPV1\u2013mediated mitochondrial calcium overload","volume":"75","author":"Xu","year":"2020","journal-title":"Cell Signal"},{"key":"B55","doi-asserted-by":"publisher","first-page":"882578","DOI":"10.3389\/fcell.2022.882578","article-title":"Role of TRPV1 in high temperature\u2013induced mitochondrial biogenesis in skeletal muscle: a mini review","volume":"10","author":"Xu","year":"2022","journal-title":"Front. Cell Dev. Biol."},{"key":"B56","doi-asserted-by":"publisher","first-page":"E317","DOI":"10.1073\/pnas.1717192115","article-title":"Heat activation is intrinsic to the pore domain of TRPV1","volume":"115","author":"Zhang","year":"2018","journal-title":"Proc. Natl. Acad. Sci. U. S. A."}],"container-title":["Frontiers in Cell and Developmental Biology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2026.1903038\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T05:33:02Z","timestamp":1789623182000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2026.1903038\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,17]]},"references-count":56,"alternative-id":["10.3389\/fcell.2026.1903038"],"URL":"https:\/\/doi.org\/10.3389\/fcell.2026.1903038","relation":{},"ISSN":["2296-634X"],"issn-type":[{"value":"2296-634X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,17]]},"article-number":"1903038"}}