Cardiac STIM1 deficiency triggers mitochondrial fission to impair electrophysiological function and exacerbate...

Stromal interaction molecule 1 (STIM1) is a sarcoplasmic reticulum Ca²⁺ sensor that links intracellular Ca²⁺ signaling to pathways governing cellular stress adaptation.

The purpose of this study was to determine whether cardiac STIM1 is a critical regulator of basal electromechanical function in the heart and whether its depletion exacerbates post-MI left ventricular dysfunction and electrophysiological (EP) remodeling.

Mice received cardiotropic adeno-associated virus serotype 9-mediated delivery of short hairpin RNA targeting STIM1 or control. 4 weeks later, cardiac function was assessed in vivo by echocardiography followed by ex vivo optical action potential mapping. Complementary studies in isolated myocytes were used to assess contractility, action potentials, and Ca²⁺ transients in vitro. Mitochondrial ultrastructure was assessed by electron microscopy, and mitochondrial dynamics protein expression was determined by immunoblotting. In a separate cohort, mice underwent in vivo ischemia/reperfusion injury, followed by comprehensive post-myocardial infarction assessment of ventricular function and EP remodeling.

Cardiac STIM1 knockdown reduced ventricular systolic function and impaired intrinsic myocyte contractility. At the tissue level, hearts exhibited slowed conduction, reduced connexin-43 expression, and pacing-induced EP instability. These abnormalities were accompanied by pronounced remodeling of mitochondrial architecture and dynamics, consistent with a shift toward enhanced fission. Functionally, STIM1-deficient myocytes displayed a marked reduction in mitochondria-enriched Rhod-2 acetoxymethyl ester Ca²⁺ transient amplitude, indicating impaired mitochondrial Ca²⁺. After ischemia/reperfusion injury, STIM1-deficient hearts developed more severe ventricular dysfunction and adverse EP remodeling, including the genesis of spatially discordant alternans.

STIM1 is a central regulator of mitochondrial function and electromechanical stability. Its loss impairs mitochondrial Ca²⁺ handling, disrupts EP function, and accelerates adverse post-MI remodeling.