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; Muniswamy Madesh; John W. Elrod

doi:10.1016/j.celrep.2015.06.017

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, Muniswamy Madesh, John W. Elrod

Research output: Contribution to journal › Article › peer-review

306 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 language	English (US)
Pages (from-to)	23-34
Number of pages	12
Journal	Cell Reports
Volume	12
Issue number	1
DOIs	https://doi.org/10.1016/j.celrep.2015.06.017
State	Published - Jul 7 2015

All Science Journal Classification (ASJC) codes

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.celrep.2015.06.017

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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., Madesh, 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

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

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.",

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

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doi = "10.1016/j.celrep.2015.06.017",

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Luongo, TS, Lambert, JP, Yuan, A, Zhang, X, Gross, P, Song, J, Shanmughapriya, S, Gao, E, Jain, M, Houser, SR, Koch, WJ, Cheung, JY, Madesh, M & Elrod, JW 2015, 'The Mitochondrial Calcium Uniporter Matches Energetic Supply with Cardiac Workload during Stress and Modulates Permeability Transition', Cell Reports, vol. 12, no. 1, pp. 23-34. https://doi.org/10.1016/j.celrep.2015.06.017

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T1 - The Mitochondrial Calcium Uniporter Matches Energetic Supply with Cardiac Workload during Stress and Modulates Permeability Transition

AU - Luongo, Timothy S.

AU - Lambert, Jonathan P.

AU - Yuan, Ancai

AU - Zhang, Xueqian

AU - Gross, Polina

AU - Song, Jianliang

AU - Shanmughapriya, Santhanam

AU - Gao, Erhe

AU - Jain, Mohit

AU - Houser, Steven R.

AU - Koch, Walter J.

AU - Cheung, Joseph Y.

AU - Madesh, Muniswamy

AU - Elrod, John W.

PY - 2015/7/7

Y1 - 2015/7/7

N2 - 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.

AB - 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.

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

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