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Given the intimate anatomical and functional coupling between the SR and mitochondria, we investigated whether TRIC-A contributes to SR\u2013mitochondrial crosstalk under cardiac stress conditions. Using a transverse aortic constriction (TAC) model, we found that TRIC-A\u2212\/\u2212 mice developed more severe cardiac hypertrophy, underwent maladaptive remodeling, and activated apoptotic pathways compared with wild-type littermates. At the cellular level, TRIC-A-deficient cardiomyocytes were more susceptible to H2O2-induced mitochondrial injury and displayed abnormal mitochondrial morphology. Live-cell imaging revealed exaggerated mitochondrial Ca2+ uptake during caffeine stimulation and increased propensity for store-overload-induced Ca2+ release (SOICR). Complementary studies in HEK293 cells expressing RyR2 demonstrated that exogenous TRIC-A expression attenuates RyR2-mediated mitochondrial Ca2+ overload, preserves respiratory function, and suppresses superoxide generation. Together, these findings identify TRIC-A as a critical regulator of SR\u2013mitochondrial Ca2+ signaling. By constraining mitochondrial Ca2+ influx and limiting oxidative stress, TRIC-A safeguards cardiomyocytes against SOICR-driven injury and confers protection against pressure overload-induced cardiac dysfunction.<\/jats:p>","DOI":"10.3390\/cells14201579","type":"journal-article","created":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T13:13:27Z","timestamp":1760361207000},"page":"1579","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["TRIC-A Facilitates Sarcoplasmic Reticulum\u2013Mitochondrial Ca2+ Signaling Crosstalk in Cardiomyocytes"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8784-4702","authenticated-orcid":false,"given":"Ang","family":"Li","sequence":"first","affiliation":[{"name":"Department of Kinesiology, College of Nursing and Health Innovation, University of Texas at Arlington, Arlington, TX 76010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyu","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Surgery, Division of Surgical Sciences, University of Virginia, Charlottesville, VA 22903, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6193-9826","authenticated-orcid":false,"given":"Ki Ho","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Surgery, Division of Surgical Sciences, University of Virginia, Charlottesville, VA 22903, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianxun","family":"Yi","sequence":"additional","affiliation":[{"name":"Department of Kinesiology, College of Nursing and Health Innovation, University of Texas at Arlington, Arlington, TX 76010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuejun","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Kinesiology, College of Nursing and Health Innovation, University of Texas at Arlington, Arlington, TX 76010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9174-5806","authenticated-orcid":false,"given":"Jae-Kyun","family":"Ko","sequence":"additional","affiliation":[{"name":"Department of Surgery, Division of Surgical Sciences, University of Virginia, Charlottesville, VA 22903, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuchen","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Surgery, Division of Surgical Sciences, University of Virginia, Charlottesville, VA 22903, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miyuki","family":"Nishi","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Kyoto University, Kyoto 606-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daiju","family":"Yamazaki","sequence":"additional","affiliation":[{"name":"Division of Pharmacology, National Institute of Health Sciences, Tokyo 158-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Takeshima","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Kyoto University, Kyoto 606-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingsong","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Kinesiology, College of Nursing and Health Innovation, University of Texas at Arlington, Arlington, TX 76010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianjie","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Surgery, Division of Surgical Sciences, University of Virginia, Charlottesville, VA 22903, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1016\/0002-9149(73)91030-8","article-title":"Quantitative electron microscopic description of heart muscle cells. 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