{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T21:22:52Z","timestamp":1788384172709,"version":"build-2803163510"},"reference-count":58,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T00:00:00Z","timestamp":1778716800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Phosphate (Pi) and calcium (Ca2+) are essential mineral ions that play coordinated roles in maintaining normal cellular functions. While various steps of calcium signaling are well characterized, emerging evidence suggests the critical role of both intracellular and extra cellular phosphate in regulating intracellular Ca2+. In the cytoplasm, phosphate influences ATP production and organelle calcium buffering and influences the activity of calcium pumps, such as sarcoplasmic\/endoplasmic reticulum Ca2+-ATPase (SERCA) and the plasma membrane Ca2+-ATPase (PMCA). Extracellular phosphate, taken up via sodium-dependent phosphate transporters, triggers signaling cascades that affect the processes of calcium influx, storage, and release. Additionally, high extracellular phosphate levels can disrupt calcium homeostasis through the systemic interactions of hormones such as fibroblast growth factor 23 (FGF23), vitamin D and parathyroid hormone (PTH), especially under pathological conditions such as chronic kidney disease (CKD). This article briefly summarizes the current understanding of the bidirectional influence of intra- and extracellular phosphate on calcium dynamics at the cellular level, with a focus on the underlying mechanisms.<\/jats:p>","DOI":"10.3390\/cells15100901","type":"journal-article","created":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T08:06:26Z","timestamp":1779696386000},"page":"901","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Phosphate-Mediated Regulation of Intracellular Calcium Dynamics"],"prefix":"10.3390","volume":"15","author":[{"given":"Huma","family":"Shahzad","sequence":"first","affiliation":[{"name":"Department of Medical Education, School of Medicine, University of Texas Rio Grande Valley (UTRGV), Edinburg, TX 78541, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1115-4550","authenticated-orcid":false,"given":"Mohammed S.","family":"Razzaque","sequence":"additional","affiliation":[{"name":"Department of Medical Education, School of Medicine, University of Texas Rio Grande Valley (UTRGV), Edinburg, TX 78541, USA"},{"name":"Center for Research and Innovation, Faculty of Medicine, Universiti Kuala Lumpur Royal College of Medicine Perak (UniKL RCMP), No. 3, Jalan Greentown, Ipoh 30450, Perak, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"a038802","DOI":"10.1101\/cshperspect.a038802","article-title":"Fundamentals of cellular calcium signaling: A primer","volume":"12","author":"Bootman","year":"2020","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"102778","DOI":"10.1016\/j.ceca.2023.102778","article-title":"Calcium as a master regulator of ferroptosis and other types of regulated necrosis","volume":"114","author":"Pedrera","year":"2023","journal-title":"Cell Calcium"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1115","DOI":"10.1073\/pnas.032427999","article-title":"Calcium signaling: A tale for all seasons","volume":"99","author":"Carafoli","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1007\/s00223-019-00636-8","article-title":"Phosphate as a signaling molecule","volume":"108","author":"Kritmetapak","year":"2021","journal-title":"Calcif. Tissue Int."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e220239","DOI":"10.1530\/EC-22-0239","article-title":"Interactions between FGF23 and vitamin D","volume":"11","author":"Razzaque","year":"2022","journal-title":"Endocr. Connect."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1038\/nrendo.2009.196","article-title":"The FGF23-Klotho axis: Endocrine regulation of phosphate homeostasis","volume":"5","author":"Razzaque","year":"2009","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Centeno, P.P., Binmahfouz, L.S., Alghamdi, K., and Ward, D.T. (2023). Inhibition of the calcium-sensing receptor by extracellular phosphate ions and by intracellular phosphorylation. Front. Physiol., 14.","DOI":"10.3389\/fphys.2023.1154374"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1016\/0005-2736(82)90266-8","article-title":"ATP-dependent calcium transport and its correlation with Ca2+\u2014ATPase activity in basolateral plasma membranes of rat duodenum","volume":"689","author":"Ghijsen","year":"1982","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1089","DOI":"10.1152\/physrev.00028.2016","article-title":"The plasma membrane calcium ATPases and their role as major new players in human disease","volume":"97","author":"Stafford","year":"2017","journal-title":"Physiol. Rev."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Steiner, P., and Zierler, S. (2025). Inter-Organellar Ca2+ Homeostasis in plant and animal systems. Cells, 14.","DOI":"10.3390\/cells14151204"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1702","DOI":"10.1038\/s12276-023-01067-0","article-title":"Phosphoinositides and intracellular calcium signaling: Novel insights into phosphoinositides and calcium coupling as negative regulators of cellular signaling","volume":"55","author":"Oh","year":"2023","journal-title":"Exp. Mol. Med."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Moccia, F., Fiorio Pla, A., Lim, D., Lodola, F., and Gerbino, A. (2023). Intracellular Ca2+ signalling: Unexpected new roles for the usual suspect. Front. Physiol., 14.","DOI":"10.3389\/fphys.2023.1210085"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1346","DOI":"10.1111\/j.1471-4159.2007.04626.x","article-title":"Calcium-induced precipitate formation in brain mitochondria: Composition, calcium capacity, and retention","volume":"102","author":"Kristian","year":"2007","journal-title":"J. Neurochem."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Malyala, S., Zhang, Y., Strubbe, J.O., and Bazil, J.N. (2019). Calcium phosphate precipitation inhibits mitochondrial energy metabolism. PLoS Comput. Biol., 15.","DOI":"10.1371\/journal.pcbi.1006719"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Walkon, L.L., Strubbe-Rivera, J.O., and Bazil, J.N. (2022). Calcium overload and mitochondrial metabolism. Biomolecules, 12.","DOI":"10.3390\/biom12121891"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1016\/j.mito.2018.11.007","article-title":"Calcium phosphate buffer formed in the mitochondrial matrix during preconditioning supports \u0394pH formation and ischemic ATP production and prolongs cell survival\u2014A hypothesis","volume":"47","author":"Dolowy","year":"2019","journal-title":"Mitochondrion"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1007\/s00395-024-01060-2","article-title":"Mitochondrial calcium in cardiac ischemia\/reperfusion injury and cardioprotection","volume":"119","author":"Bertero","year":"2024","journal-title":"Basic Res. Cardiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"11389","DOI":"10.1073\/pnas.1513047112","article-title":"Mitochondrial calcium overload is a key determinant in heart failure","volume":"112","author":"Santulli","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1186\/s13395-021-00280-7","article-title":"The Sarcoendoplasmic reticulum calcium ATPase (SERCA) pump: A potential target for intervention in aging and skeletal muscle pathologies","volume":"11","author":"Xu","year":"2021","journal-title":"Skelet. Muscle"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"C1502","DOI":"10.1152\/ajpcell.00273.2005","article-title":"Calcium phosphate precipitation in the sarcoplasmic reticulum reduces action potential-mediated Ca2+ release in mammalian skeletal muscle","volume":"289","author":"Dutka","year":"2005","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"a004317","DOI":"10.1101\/cshperspect.a004317","article-title":"Endoplasmic-reticulum calcium depletion and disease","volume":"3","author":"Mekahli","year":"2011","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1165\/rcmb.2005-0477OC","article-title":"Elevated inorganic phosphate stimulates Akt-ERK1\/2-Mnk1 signaling in human lung cells","volume":"35","author":"Chang","year":"2006","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"4693","DOI":"10.1038\/s41467-019-12399-9","article-title":"Phosphate acts directly on the calcium-sensing receptor to stimulate parathyroid hormone secretion","volume":"10","author":"Centeno","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"F470","DOI":"10.1152\/ajprenal.90538.2008","article-title":"FGF23-mediated regulation of systemic phosphate homeostasis: Is Klotho an essential player?","volume":"296","author":"Razzaque","year":"2009","journal-title":"Am. J. Physiol. Ren. Physiol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1072","DOI":"10.1038\/ki.2014.316","article-title":"Molecular interactions of FGF23 and PTH in phosphate regulation","volume":"86","author":"Lanske","year":"2014","journal-title":"Kidney Int."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Portales-Castillo, I., and Simic, P. (2022). PTH, FGF-23, Klotho and Vitamin D as regulators of calcium and phosphorus: Genetics, epigenetics and beyond. Front. Endocrinol., 13.","DOI":"10.3389\/fendo.2022.992666"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1161\/CIRCGENETICS.108.847814","article-title":"In vivo genetic evidence for suppressing vascular and soft-tissue calcification through the reduction of serum phosphate levels, even in the presence of high serum calcium and 1,25-dihydroxyvitamin d levels","volume":"2","author":"Ohnishi","year":"2009","journal-title":"Circ. Cardiovasc. Genet."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1159\/000368524","article-title":"Inhibition of phosphate-induced vascular smooth muscle cell osteo-\/chondrogenic signaling and calcification by bafilomycin A1 and methylamine","volume":"40","author":"Alesutan","year":"2015","journal-title":"Kidney Blood Press. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1205","DOI":"10.1159\/000485874","article-title":"High phosphate-induced calcification of vascular smooth muscle cells is associated with the TLR4\/NF-\u03bab signaling pathway","volume":"42","author":"Zhang","year":"2017","journal-title":"Kidney Blood Press. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"e20997","DOI":"10.1096\/fj.202000799RR","article-title":"High phosphate actively induces cytotoxicity by rewiring pro-survival and pro-apoptotic signaling networks in HEK293 and HeLa cells","volume":"35","author":"He","year":"2021","journal-title":"FASEB J."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1172\/JCI120848","article-title":"Mitochondria, OxPhos, and neurodegeneration: Cells are not just running out of gas","volume":"129","author":"Schon","year":"2019","journal-title":"J. Clin. Investig."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Montilla, M., Pavas-Escobar, N., Guatibonza-Ar\u00e9valo, I.M., M\u00fanera, A., Rivera-Melo, R.E., and Ruiz, F.A. (2025). Inorganic polyphosphate: An emerging regulator of neuronal bioenergetics and its implications in neuroprotection. Biomolecules, 15.","DOI":"10.3390\/biom15081060"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1007\/978-3-030-91623-7_13","article-title":"Phosphate dysregulation and neurocognitive sequelae","volume":"1362","author":"Acquaviva","year":"2022","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Liu, S.Q., Troy, J.B., Goldman, J., and Guillory, R.J. (2025). Calcium phosphate formation and deposition in ischemic neurons. PLoS ONE, 20.","DOI":"10.1371\/journal.pone.0317055"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2146","DOI":"10.1038\/s41467-020-16074-2","article-title":"Increased mitochondrial calcium levels associated with neuronal death in a mouse model of Alzheimer\u2019s disease","volume":"11","author":"Hou","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Brown, R.B. (2022). Parkinson\u2019s disease etiology: Insights and associations with phosphate toxicity. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23158060"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Zhou, C., Shi, Z., Ouyang, N., and Ruan, X. (2021). Hyperphosphatemia and cardiovascular disease. Front. Cell Dev. Biol., 9.","DOI":"10.3389\/fcell.2021.644363"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Shi, M., Shepard, S., Zhou, Z., Maique, J., Seli, O., Moe, O.W., and Hu, M.C. (2021). High dietary phosphate exacerbates and acts independently of low autophagy activity in pathological cardiac remodeling and dysfunction. Cells, 10.","DOI":"10.3390\/cells10040777"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1161\/ATVBAHA.123.319198","article-title":"Phosphate in cardiovascular disease: From new insights into molecular mechanisms to clinical implications","volume":"44","author":"Turner","year":"2024","journal-title":"Arter. Thromb. Vasc. Biol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1","DOI":"10.5551\/jat.RV22012","article-title":"Phosphate and coronary artery disease in patients with chronic kidney disease","volume":"31","author":"Ogata","year":"2024","journal-title":"J. Atheroscler. Thromb."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"822","DOI":"10.1161\/CIRCULATIONAHA.109.890954","article-title":"Ca2+ cycling and new therapeutic approaches for heart failure","volume":"121","author":"Hajjar","year":"2010","journal-title":"Circulation"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"21446","DOI":"10.18632\/aging.103896","article-title":"High phosphate induces skeletal muscle atrophy and suppresses myogenic differentiation by increasing oxidative stress and activating Nrf2 signaling","volume":"12","author":"Chung","year":"2020","journal-title":"Aging"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1007","DOI":"10.1152\/japplphysiol.00818.2023","article-title":"Association between dietary phosphate intake and skeletal muscle energetics in adults without cardiovascular disease","volume":"136","author":"Giacona","year":"2024","journal-title":"J. Appl. Physiol."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Hern\u00e1ndez-Ochoa, E.O., Pratt, S.J.P., Lovering, R.M., and Schneider, M.F. (2015). Critical role of intracellular RyR1 calcium release channels in skeletal muscle function and disease. Front. Physiol., 6.","DOI":"10.3389\/fphys.2015.00420"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1038\/ki.1983.125","article-title":"Impaired energy metabolism in skeletal muscle during phosphate depletion","volume":"24","author":"Brautbar","year":"1983","journal-title":"Kidney Int."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"e74782","DOI":"10.7554\/eLife.74782","article-title":"Hyperphosphatemia increases inflammation to exacerbate anemia and skeletal muscle wasting independently of FGF23-FGFR4 signaling","volume":"11","author":"Czaya","year":"2022","journal-title":"Elife"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1161\/CIRCULATIONAHA.120.052384","article-title":"Cooperative binding of ETS2 and NFAT links Erk1\/2 and calcineurin signaling in the pathogenesis of cardiac hypertrophy","volume":"144","author":"Luo","year":"2021","journal-title":"Circulation"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.yjmcc.2019.11.149","article-title":"FGF23 induced left ventricular hypertrophy mediated by FGFR4 signaling in the myocardium is attenuated by soluble Klotho in mice","volume":"138","author":"Han","year":"2020","journal-title":"J. Mol. Cell Cardiol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1080\/14728222.2025.2482552","article-title":"Can targeting the FGF23-\u03b1Klotho signaling system delay phosphate-driven organ damage?","volume":"29","author":"Razzaque","year":"2025","journal-title":"Expert. Opin. Ther. Targets"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"C904","DOI":"10.1152\/ajpcell.01020.2024","article-title":"Asymmetric FGF receptor dimerization: Implications for FGF23 biology and drug discovery","volume":"329","author":"Razzaque","year":"2025","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"107613","DOI":"10.1016\/j.jsb.2020.107613","article-title":"Intracellular calcium phosphate deposits contribute to transcellular calcium transport within the hepatopancreas of Porcellio scaber","volume":"212","author":"Rupp","year":"2020","journal-title":"J. Struct. Biol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"610","DOI":"10.1210\/edrv-14-5-610","article-title":"The inositol phosphate-calcium signaling system in nonexcitable cells","volume":"14","author":"Putney","year":"1993","journal-title":"Endocr. Rev."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"596","DOI":"10.1038\/nature08030","article-title":"NAADP mobilizes calcium from acidic organelles through two-pore channels","volume":"459","author":"Calcraft","year":"2009","journal-title":"Nature"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"15642","DOI":"10.1038\/s41598-019-52194-6","article-title":"A novel phospho-modulatory mechanism contributes to the calcium-dependent regulation of T-type Ca2+ channels","volume":"9","author":"Chemin","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"e84282","DOI":"10.7554\/eLife.84282","article-title":"Phosphate starvation signaling increases mitochondrial membrane potential through respiration-independent mechanisms","volume":"13","author":"Ouyang","year":"2024","journal-title":"Elife"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1040","DOI":"10.34067\/KID.0000000820","article-title":"The pathologic actions of phosphate in CKD","volume":"6","author":"Fajol","year":"2025","journal-title":"Kidney360"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1215","DOI":"10.1210\/jcem.85.3.6456","article-title":"Close correlation between estrogen treatment and renal phosphate reabsorption capacity","volume":"85","author":"Uemura","year":"2000","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1080\/0886022X.2021.1901739","article-title":"Estrogen and estrogen receptors in kidney diseases","volume":"43","author":"Ma","year":"2021","journal-title":"Ren. Fail."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/10\/901\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T08:12:57Z","timestamp":1779696777000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/10\/901"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,14]]},"references-count":58,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2026,5]]}},"alternative-id":["cells15100901"],"URL":"https:\/\/doi.org\/10.3390\/cells15100901","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,14]]}}}