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Mitochondria dynamically adapt to fluctuating energy demands, yet the mechanisms underlying the adaptions remain poorly understood. Here, we employed real-time intravital imaging and fluorescence lifetime imaging microscopy (FLIM) to monitor mitochondria functions in submandibular glands. We revealed distinct mitochondrial distribution patterns; in acinar cells, mitochondria were predominantly distributed near the cell membranes or scattered throughout the cytoplasm with extensive endoplasmic reticulum (ER)\u2013mitochondria contact sites, whereas in ductal cells, mitochondria were densely packed within the cytoplasm. At resting states, mitochondria exhibited larger volumes, fewer numbers, and higher oxidative phosphorylation activity in acinar cells compared with those in ductal cells. Upon stimulation with pilocarpine, mitochondrial motility, NAD(P)H levels, NAD(P)H enzyme\u2013bound fractions, and mitochondrial adenosine triphosphate (ATP) production were significantly elevated. Pilocarpine-induced secretion, mediated by both aquaporin 5 translocation and the opening of paracellular pathway, was markedly attenuated by oligomycin A, an ATP synthase inhibitor. Notably, pilocarpine increased mitochondria\u2013ER contact sites to 1.7 times the control level (from 18% to 31%), and blocking mitochondrial calcium uptake significantly suppressed pilocarpine-induced NAD(P)H and ATP production. These findings highlight the critical role of ER\u2013mitochondria calcium transfer in sustaining bioenergetics required for salivary secretion, providing new insights into mitochondrial functional adaptation and its physiological significance in intact secretory systems.<\/jats:p>","DOI":"10.1177\/00220345251411909","type":"journal-article","created":{"date-parts":[[2026,2,24]],"date-time":"2026-02-24T12:00:46Z","timestamp":1771934446000},"page":"1328-1338","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":0,"title":["Endoplasmic Reticulum\u2013Mitochondria Calcium Drives Salivary Bioenergetics"],"prefix":"10.1177","volume":"105","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7016-0016","authenticated-orcid":false,"given":"S.N.","family":"Min","sequence":"first","affiliation":[{"name":"Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology &amp; National Center for Stomatology &amp; National Clinical Research Center for Oral Diseases &amp; National Engineering Research Center of Oral Biomaterials and Digital Medical Devices &amp; Beijing Key Laboratory of Digital Stomatology &amp; NHC Key Laboratory of Digital Stomatology &amp; NMPA Key Laboratory for Dental Materials, Beijing, P.R. China"},{"name":"First Clinical Division, Peking University School and Hospital of Stomatology, Beijing, P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"X.D.","family":"Mao","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pathophysiology, Peking University School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, P.R. 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