Adaptation to Elevated Mitochondrial Calcium Is Distinct in the Left and Right Ventricles.

Abstract

BACKGROUND Mitochondrial ATP production, essential for cardiomyocyte function, is regulated by mitochondrial Ca2+ (mtCa2+). The primary route for mtCa2+ influx is the mitochondrial calcium uniporter complex. The mitochondrial calcium uniporter complex subunit MICU (mitochondrial calcium uptake) 1 limits mtCa2+ uptake, preventing mtCa2+ overload. Although elevated mtCa2+ has been observed in multiple diseases including heart failure, its effects on heart function remain elusive. METHODS To investigate the impact of elevated mtCa2+ in adult hearts, we generated a mouse model with cardiomyocyte-specific tamoxifen-inducible Micu1 deletion (Micu1cKO). Cardiac function was assessed through echocardiography. Mitochondria, adult cardiomyocytes, and tissue extracts were isolated from the left ventricle (LV) and right ventricle (RV) for comprehensive analysis at multiple time points ranging from 1 to 9 weeks post-tamoxifen injection. RESULTS Acute MICU1 deficiency resulted in increased mtCa2+ accompanied by reduced mitochondrial respiration in both the RV and LV. Contractile function, which was diminished in both ventricles initially, remained reduced in the RV upon prolonged MICU1 deficiency. In contrast, the LV exhibited signs of recovery over time, including restored ejection fraction concurrent with normalization of mtCa2+ levels. This pattern was mirrored in cardiomyocyte contractility. In Micu1cKO RV, mtCa2+ remained elevated, likely contributing to oxidative stress. As a potential mechanism underlying LV-specific recovery, EMRE (essential MCU regulator), an mitochondrial calcium uniporter complex subunit that promotes mtCa2+ uptake, was found to be downregulated only in the LV. This suggested that the LV initiated a compensatory response to elevated mtCa2+, while the RV remained impacted. Supporting this, proteomics analysis indicated a divergent proteomic signature in Micu1cKO RV. Follow-up experiments suggested enhanced EMRE degradation in Micu1cKO LV mediated by m-AAA proteases through a PKA (protein kinase A)-regulated mechanism. In MICU1-deficient neonatal cardiomyocytes, pharmacological PKA inhibition was sufficient to decrease EMRE levels. Analysis of LV tissues from patients with dilated cardiomyopathy suggested that this pathway may be relevant in human DCM. CONCLUSIONS While elevated mtCa2+ disrupted cardiac function in both ventricles, it induced an LV-specific adaptive response that suppressed mtCa2+ intake, contributing to the recovery of mitochondrial and cardiac function. The absence of this pathway in the RV has implications for therapeutics targeting RV dysfunction, a key determinant of mortality in heart failure.