TRIC-A Facilitates Sarcoplasmic Reticulum–Mitochondrial Ca2+ Signaling Crosstalk in Cardiomyocytes

TRIC-A is an intracellular cation channel enriched in excitable tissues that is recently identified as a key modulator of sarcoplasmic reticulum (SR) Ca2+ homeostasis through direct interaction with type 2 ryanodine receptors (RyR2). Given the intimate anatomical and functional coupling between the SR and mitochondria, we investigated whether TRIC-A contributes to SR–mitochondrial crosstalk under cardiac stress conditions. Using a transverse aortic constriction (TAC) model, we found that TRIC-A−/− 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–mitochondrial 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.