The Mitochondrial Calcium Uniporter Matches Energetic Supply with Cardiac Workload during Stress and Modulates Permeability Transition

Timothy S. Luongo, Jonathan P. Lambert, Ancai Yuan, Xueqian Zhang, Polina Gross, Jianliang Song, Santhanam Shanmughapriya, Erhe Gao, Mohit Jain, Steven R. Houser, Walter J. Koch, Joseph Y. Cheung, Madesh Muniswamy, John W. Elrod

Research output: Contribution to journalArticle

154 Scopus citations

Abstract

Cardiac contractility is mediated by a variable flux in intracellular calcium (Ca2+), thought to be integrated into mitochondria via the mitochondrial calcium uniporter (MCU) channel to match energetic demand. Here, we examine a conditional, cardiomyocyte-specific, mutant mouse lacking Mcu, the pore-forming subunit of the MCU channel, in adulthood. Mcu-/- mice display no overt baseline phenotype and are protected against mCa2+ overload in an invivo myocardial ischemia-reperfusion injury model by preventing the activation of the mitochondrial permeability transition pore, decreasing infarct size, and preserving cardiac function. In addition, we find that Mcu-/- mice lack contractile responsiveness to acute β-adrenergic receptor stimulation and in parallel are unable to activate mitochondrial dehydrogenases and display reduced bioenergetic reserve capacity. These results support the hypothesis that MCU may be dispensable for homeostatic cardiac function but required to modulate Ca2+-dependent metabolism during acute stress.

Original languageEnglish (US)
Pages (from-to)23-34
Number of pages12
JournalCell Reports
Volume12
Issue number1
DOIs
StatePublished - Jul 7 2015
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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  • Cite this

    Luongo, T. S., Lambert, J. P., Yuan, A., Zhang, X., Gross, P., Song, J., Shanmughapriya, S., Gao, E., Jain, M., Houser, S. R., Koch, W. J., Cheung, J. Y., Muniswamy, M., & Elrod, J. W. (2015). The Mitochondrial Calcium Uniporter Matches Energetic Supply with Cardiac Workload during Stress and Modulates Permeability Transition. Cell Reports, 12(1), 23-34. https://doi.org/10.1016/j.celrep.2015.06.017