Abstract P3205: Differential Adaptation To Mitochondrial Ca 2+ Overload In The Left And Right Ventricles

Abstract

Mitochondrial Ca 2+ (mtCa 2+ ) overload has emerged as a potential contributor to heart failure (HF), possibly through inducing oxidative stress. In HF, right ventricular (RV) function is predictive of mortality, and the RV is more vulnerable to oxidative stress than the left ventricle (LV). Therefore, how the response to mtCa 2+ overload might differ in the RV and LV is critical; however, ventricle-specific mtCa 2+ handling is still poorly understood. We sought to induce cardiac mtCa 2+ overload via genetic manipulation of the mitochondrial calcium uniporter complex (mtCU) formed by the MCU pore and several regulatory subunits. mtCU stoichiometry shapes mtCa 2+ kinetics: loss of mitochondrial calcium uptake 1 (MICU1) induces mtCa 2+ overload, and reduced essential MCU regulator (EMRE) to MCU ratio decreases mtCa 2+ uptake rate. Hypothesizing that mtCa 2+ overload differentially affects LV and RV function, we generated tamoxifen (Tmx)-inducible cardiac-specific Micu1 knockout mice ( Micu1 cKO ) . After confirming that MICU1 loss at 1 week post-Tmx resulted in mtCa 2+ overload in both ventricles, we explored how the LV and RV responses diverge. In Micu1 cKO mice, LV function assessed by echocardiography declined at 4 weeks post-Tmx but recovered partially by 6 weeks. However, impaired RV function at 4 weeks post-Tmx persisted at 6 weeks and longer, without evidence of pulmonary hypertension. Interestingly, at 7-9 weeks post-Tmx, mtCa 2+ levels and oxidative stress remained elevated in the RV but returned to control levels in the LV. Concurrently, EMRE protein levels and mtCa 2+ uptake rate were reduced only in the LV, suggesting that the LV has greater capacity to adapt to mtCa 2+ overload via downregulation of EMRE. We further traced this LV-specific adaptive response to increased maturation of the mAAA-proteases that degrade EMRE. In summary, mtCa 2+ overload induced by MICU1 deletion results in greater oxidative stress and functional impairment over time in the RV than the LV due to absence of compensatory EMRE reduction in the RV.