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, Mark E. Anderson

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article number7081
JournalNature communications
Volume6
DOIs
StatePublished - Jan 20 2015

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ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Wu, Y., Rasmussen, T. P., Koval, O. M., Joiner, M. L. A., Hall, D. D., Chen, B., Luczak, E. D., Wang, Q., Rokita, A. G., Wehrens, X. H. T., Song, L. S., & Anderson, M. E. (2015). The mitochondrial uniporter controls fight or flight heart rate increases. Nature communications, 6, [7081]. https://doi.org/10.1038/ncomms7081