The mitochondrial uniporter controls fight or flight heart rate increases

Yuejin Wu (), Tyler P. Rasmussen, Olha M Koval, Mei-ling A. Joiner, Duane D. Hall, Biyi Chen, Elizabeth D. Luczak, Qiongling Wang, Adam G. Rokita, Xander H.T. Wehrens, Long-Sheng Song and Mark E. Anderson ()
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Yuejin Wu: Carver College of Medicine, The University of Iowa
Tyler P. Rasmussen: Carver College of Medicine, The University of Iowa
Olha M Koval: Carver College of Medicine, The University of Iowa
Mei-ling A. Joiner: Carver College of Medicine, The University of Iowa
Duane D. Hall: Carver College of Medicine, The University of Iowa
Biyi Chen: Carver College of Medicine, The University of Iowa
Elizabeth D. Luczak: Carver College of Medicine, The University of Iowa
Qiongling Wang: Cardiovascular Research Institute, Baylor College of Medicine
Adam G. Rokita: Carver College of Medicine, The University of Iowa
Xander H.T. Wehrens: Cardiovascular Research Institute, Baylor College of Medicine
Long-Sheng Song: Carver College of Medicine, The University of Iowa
Mark E. Anderson: Carver College of Medicine, The University of Iowa

Nature Communications, 2015, vol. 6, issue 1, 1-13

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms7081

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