Abstract 366: The Role of Mitochondrial Calcium Uniporter Complex in Cardiac Contractility and Function
Tomar, D; Shanmughapriya, S; Roy, R; Zhang, X; Song, J; Schumacher, SM; Madesh, M; Cheung, JY; Koch, WJ; Rajan, S
Published in: Circulation Research
Cardiac contractility is regulated by the intracellular Ca
concentration fluxes which are maintained by multiple channels and transporters. Mitochondrial Calcium Uniporter (MCU) is the highly selective Ca
ion channel responsible for the electrophoretic Ca
uptake into the mitochondrial matrix. Earlier studies on the cardiac-specific acute MCU knockout and transgenic dominant-negative MCU mice have demonstrated that mitochondrial Ca
(
Ca
) signaling is necessary for cardiac ‘‘fight-or-flight’’ contractile response, however, the role of
Ca
in the beat-to-beat regulation of cardiac contractility is highly debated. The MCU channel function is regulated by varied molecular regulatory components as well as ROS mediated modification at the Cys-96 residue of the core MCU protein. Our earlier studies have demonstrated that loss of MCU Regulator 1 (MCUR1) in cardiomyocytes results in the impaired
Ca
uptake. To dissect the precise role of MCU in regulating cytosolic Ca
transients associated with excitation-contraction (E-C) coupling and cardiac functions, we have employed the loss-of-function, cardiac-specific MCUR1 knockout mouse and a gain-of-function MCU
knockin mouse generated by CRISPR/Cas9 approach. Using these novel mouse models, both by in vivo analyses of cardiac physiology and in vitro experiments including single-cell cardiac contractility, calcium transients, and electrophysiology measurements, our study demonstrates that
Ca
buffering actively participates in E-C coupling. MCUR1/MCU regulated
Ca
buffering in cardiomyocytes, although insignificant under basal condition, becomes critical in stress-induced conditions and actively participates in regulating the
Ca
transients during adrenergic stimulation. Our data indicate that MCUR1 ablation offers protection against pressure-overload cardiac hypertrophy and MCU
KI mice exhibit significantly decreased LV ejection fraction at baseline. In summary, our results provide critical insights into the mechanisms by which the MCU channel contributes in regulating the contractile function of the cardiomyocytes and the role of
Ca
in the development and progression of heart failure.
