@article{e0a0ecacbaf044e980d6e279a330964f,
title = "The mitochondrial uniporter controls fight or flight heart rate increases",
abstract = "Heart rate increases are a fundamental adaptation to physiological stress, while inappropriate heart rate increases are resistant to current therapies. However, the metabolic mechanisms driving heart rate acceleration in cardiac pacemaker cells remain incompletely understood. The mitochondrial calcium uniporter (MCU) facilitates calcium entry into the mitochondrial matrix to stimulate metabolism. We developed mice with myocardial MCU inhibition by transgenic expression of a dominant-negative (DN) MCU. Here, we show that DN-MCU mice had normal resting heart rates but were incapable of physiological fight or flight heart rate acceleration. We found that MCU function was essential for rapidly increasing mitochondrial calcium in pacemaker cells and that MCU-enhanced oxidative phoshorylation was required to accelerate reloading of an intracellular calcium compartment before each heartbeat. Our findings show that MCU is necessary for complete physiological heart rate acceleration and suggest that MCU inhibition could reduce inappropriate heart rate increases without affecting resting heart rate.",
author = "Yuejin Wu and Rasmussen, {Tyler P.} and Koval, {Olha M.} and Joiner, {Mei Ling A.} and Hall, {Duane D.} and Biyi Chen and Luczak, {Elizabeth D.} and Qiongling Wang and Rokita, {Adam G.} and Wehrens, {Xander H.T.} and Song, {Long Sheng} and Anderson, {Mark E.}",
note = "Funding Information: The authors thank Shawn Roach and Catherine E. Kiefe for graphic contributions, Rajan Sah, Peter M. Snyder and Leonid V. Zingman for their criticisms and suggestions, William J. Kutschke and Jinying Yang for technical support, Nicholas R. Wilson and Katrina Dion for experimental assistance and The University of Iowa Gene Transfer Vector Core for providing adenoviral agents. This work was supported by National Institutes of Health (NIH) Grants R01-HL079031, R01-HL096652, R01-HL070250 and R01-HL113001 to M.E.A., R01-HL089598 and R01-HL117641 to X.H.T.W. and F30-HL114258 to T.P.R. Funding Information: The authors thank Shawn Roach and Catherine E. Kiefe for graphic contributions, Rajan Sah, Peter M. Snyder and Leonid V. Zingman for their criticisms and suggestions, William J. Kutschke and Jinying Yang for technical support, Nicholas R. Wilson and Katrina Dion for experimental assistance and The University of Iowa Gene Transfer Vector Core for providing adenoviral agents. This work was supported by National Institutes of Health (NIH) Grants R01-HL079031, R01-HL096652, R01-HL070250 and R01-HL113001 to M.E.A., R01-HL089598 and R01-HL117641 to X.H.T.W. and F30HL114258 to T.P.R. Publisher Copyright: {\textcopyright} 2015 Macmillan Publishers Limited. All rights reserved.",
year = "2015",
month = jan,
day = "20",
doi = "10.1038/ncomms7081",
language = "English (US)",
volume = "6",
journal = "Nature communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
}