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Abstract 366: The Role of Mitochondrial Calcium Uniporter Complex in Cardiac Contractility and Function

Publication ,  Conference
Tomar, D; Shanmughapriya, S; Roy, R; Zhang, X; Song, J; Schumacher, SM; Madesh, M; Cheung, JY; Koch, WJ; Rajan, S
Published in: Circulation Research
August 3, 2018

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.

Duke Scholars

Published In

Circulation Research

DOI

EISSN

1524-4571

ISSN

0009-7330

Publication Date

August 3, 2018

Volume

123

Issue

Suppl_1

Publisher

Ovid Technologies (Wolters Kluwer Health)

Related Subject Headings

  • Cardiovascular System & Hematology
  • 3202 Clinical sciences
  • 3201 Cardiovascular medicine and haematology
  • 1103 Clinical Sciences
  • 1102 Cardiorespiratory Medicine and Haematology
 

Citation

APA
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MLA
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Tomar, D., Shanmughapriya, S., Roy, R., Zhang, X., Song, J., Schumacher, S. M., … Rajan, S. (2018). Abstract 366: The Role of Mitochondrial Calcium Uniporter Complex in Cardiac Contractility and Function. In Circulation Research (Vol. 123). Ovid Technologies (Wolters Kluwer Health). https://doi.org/10.1161/res.123.suppl_1.366
Tomar, Dhanendra, Santhanam Shanmughapriya, Rajika Roy, Xueqian Zhang, Jianliang Song, Sarah M. Schumacher, Muniswamy Madesh, Joseph Y. Cheung, Walter J. Koch, and Sudarsan Rajan. “Abstract 366: The Role of Mitochondrial Calcium Uniporter Complex in Cardiac Contractility and Function.” In Circulation Research, Vol. 123. Ovid Technologies (Wolters Kluwer Health), 2018. https://doi.org/10.1161/res.123.suppl_1.366.
Tomar D, Shanmughapriya S, Roy R, Zhang X, Song J, Schumacher SM, et al. Abstract 366: The Role of Mitochondrial Calcium Uniporter Complex in Cardiac Contractility and Function. In: Circulation Research. Ovid Technologies (Wolters Kluwer Health); 2018.
Tomar, Dhanendra, et al. “Abstract 366: The Role of Mitochondrial Calcium Uniporter Complex in Cardiac Contractility and Function.” Circulation Research, vol. 123, no. Suppl_1, Ovid Technologies (Wolters Kluwer Health), 2018. Crossref, doi:10.1161/res.123.suppl_1.366.
Tomar D, Shanmughapriya S, Roy R, Zhang X, Song J, Schumacher SM, Madesh M, Cheung JY, Koch WJ, Rajan S. Abstract 366: The Role of Mitochondrial Calcium Uniporter Complex in Cardiac Contractility and Function. Circulation Research. Ovid Technologies (Wolters Kluwer Health); 2018.

Published In

Circulation Research

DOI

EISSN

1524-4571

ISSN

0009-7330

Publication Date

August 3, 2018

Volume

123

Issue

Suppl_1

Publisher

Ovid Technologies (Wolters Kluwer Health)

Related Subject Headings

  • Cardiovascular System & Hematology
  • 3202 Clinical sciences
  • 3201 Cardiovascular medicine and haematology
  • 1103 Clinical Sciences
  • 1102 Cardiorespiratory Medicine and Haematology