TRIC-A Loss Sensitizes the Heart to β-Adrenergic Stress and Drives Cardiomyocyte Death and Fibrosis

Trimeric intracellular cation channel A (TRIC-A) provides counter-ion support for sarcoplasmic reticulum (SR) Ca²⁺ release, yet its physiological role in the intact heart under stress remains poorly defined. Here, we demonstrate that TRIC-A is essential for maintaining balanced SR Ca²⁺ release, mitochondrial integrity, and cardiac resilience during β-adrenergic stimulation. Tric-a^-/- cardiomyocytes exhibited Ca²⁺ transients evoked by electrical stimuli and exaggerated isoproterenol (ISO)-evoked Ca²⁺ release, consistent with SR Ca²⁺ overload. These defects were accompanied by selective upregulation of protein kinase A (PKA)-dependent phosphorylation of ryanodine receptor 2 (RyR2) (S2808) and phospholamban (PLB) (S16). Acute ISO challenge induced mitochondrial swelling, cristae disruption, and Evans Blue Dye uptake, and elevated circulating troponin T in Tric-a^-/- hearts, hallmarks of necrosis-like cell death. Mitochondrial Ca²⁺ uptake inhibition with Ru360 markedly reduced membrane injury, establishing mitochondrial Ca²⁺ overload as the proximal trigger of cardiac cell death. With sustained β-adrenergic stimulation by ISO, Tric-a^-/- hearts developed extensive interstitial and perivascular fibrosis without exaggerated hypertrophy. Cardiac fibroblasts lacked TRIC-A expression and displayed normal Ca²⁺ signaling and activation, indicating that fibrosis arises secondarily from cardiomyocyte injury rather than fibroblast-intrinsic abnormalities. These findings identify TRIC-A as a critical regulator of SR-mitochondrial Ca²⁺ coupling and a key molecular safeguard that protects the heart from catecholamine-induced injury and maladaptive remodeling.