The Mitochondrial Calcium Uniporter Selectively Matches Metabolic Output to Acute Contractile Stress in the Heart

Jennifer Q. Kwong, Xiyuan Lu, Robert N. Correll, Jennifer A. Schwanekamp, Ronald J. Vagnozzi, Michelle A. Sargent, Allen J. York, Jianyi Zhang, Donald M Bers, Jeffery D. Molkentin

Research output: Contribution to journalArticle

119 Citations (Scopus)

Abstract

In the heart, augmented Ca<sup>2+</sup> fluxing drives contractility and ATP generation through mitochondrial Ca<sup>2+</sup> loading. Pathologic mitochondrial Ca<sup>2+</sup> overload with ischemic injury triggers mitochondrial permeability transition pore (MPTP) opening and cardiomyocyte death. Mitochondrial Ca<sup>2+</sup> uptake is primarily mediated by the mitochondrial Ca<sup>2+</sup> uniporter (MCU). Here, we generated mice with adult and cardiomyocyte-specific deletion of Mcu, which produced mitochondria refractory to acute Ca<sup>2+</sup> uptake, with impaired ATP production, and inhibited MPTP opening upon acute Ca<sup>2+</sup> challenge. Mice lacking Mcu inthe adult heart were also protected from acute ischemia-reperfusion injury. However, resting/basal mitochondrial Ca<sup>2+</sup> levels were normal in hearts of Mcu-deleted mice, and mitochondria lacking MCU eventually loaded with Ca<sup>2+</sup> after stress stimulation. Indeed, Mcu-deleted mice were unable to immediately sprint on a treadmill unless warmed up for 30min. Hence, MCU is a dedicated regulator of short-term mitochondrial Ca<sup>2+</sup> loading underlying a"fight-or-flight" response that acutely matches cardiac workload with ATP production.

Original languageEnglish (US)
Pages (from-to)15-22
Number of pages8
JournalCell Reports
Volume12
Issue number1
DOIs
StatePublished - Jul 7 2015

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Mitochondria
Adenosine Triphosphate
Cardiac Myocytes
Exercise equipment
Refractory materials
Workload
Reperfusion Injury
mitochondrial calcium uniporter
Wounds and Injuries
mitochondrial permeability transition pore

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Kwong, J. Q., Lu, X., Correll, R. N., Schwanekamp, J. A., Vagnozzi, R. J., Sargent, M. A., ... Molkentin, J. D. (2015). The Mitochondrial Calcium Uniporter Selectively Matches Metabolic Output to Acute Contractile Stress in the Heart. Cell Reports, 12(1), 15-22. https://doi.org/10.1016/j.celrep.2015.06.002

The Mitochondrial Calcium Uniporter Selectively Matches Metabolic Output to Acute Contractile Stress in the Heart. / Kwong, Jennifer Q.; Lu, Xiyuan; Correll, Robert N.; Schwanekamp, Jennifer A.; Vagnozzi, Ronald J.; Sargent, Michelle A.; York, Allen J.; Zhang, Jianyi; Bers, Donald M; Molkentin, Jeffery D.

In: Cell Reports, Vol. 12, No. 1, 07.07.2015, p. 15-22.

Research output: Contribution to journalArticle

Kwong, JQ, Lu, X, Correll, RN, Schwanekamp, JA, Vagnozzi, RJ, Sargent, MA, York, AJ, Zhang, J, Bers, DM & Molkentin, JD 2015, 'The Mitochondrial Calcium Uniporter Selectively Matches Metabolic Output to Acute Contractile Stress in the Heart', Cell Reports, vol. 12, no. 1, pp. 15-22. https://doi.org/10.1016/j.celrep.2015.06.002
Kwong, Jennifer Q. ; Lu, Xiyuan ; Correll, Robert N. ; Schwanekamp, Jennifer A. ; Vagnozzi, Ronald J. ; Sargent, Michelle A. ; York, Allen J. ; Zhang, Jianyi ; Bers, Donald M ; Molkentin, Jeffery D. / The Mitochondrial Calcium Uniporter Selectively Matches Metabolic Output to Acute Contractile Stress in the Heart. In: Cell Reports. 2015 ; Vol. 12, No. 1. pp. 15-22.
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