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 language | English (US) |
|---|---|
| Pages (from-to) | 15-22 |
| Number of pages | 8 |
| Journal | Cell Reports |
| Volume | 12 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jul 7 2015 |
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ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)
Cite this
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 journal › Article
}
TY - JOUR
T1 - The Mitochondrial Calcium Uniporter Selectively Matches Metabolic Output to Acute Contractile Stress in the Heart
AU - Kwong, Jennifer Q.
AU - Lu, Xiyuan
AU - Correll, Robert N.
AU - Schwanekamp, Jennifer A.
AU - Vagnozzi, Ronald J.
AU - Sargent, Michelle A.
AU - York, Allen J.
AU - Zhang, Jianyi
AU - Bers, Donald M
AU - Molkentin, Jeffery D.
PY - 2015/7/7
Y1 - 2015/7/7
N2 - In the heart, augmented Ca2+ fluxing drives contractility and ATP generation through mitochondrial Ca2+ loading. Pathologic mitochondrial Ca2+ overload with ischemic injury triggers mitochondrial permeability transition pore (MPTP) opening and cardiomyocyte death. Mitochondrial Ca2+ uptake is primarily mediated by the mitochondrial Ca2+ uniporter (MCU). Here, we generated mice with adult and cardiomyocyte-specific deletion of Mcu, which produced mitochondria refractory to acute Ca2+ uptake, with impaired ATP production, and inhibited MPTP opening upon acute Ca2+ challenge. Mice lacking Mcu inthe adult heart were also protected from acute ischemia-reperfusion injury. However, resting/basal mitochondrial Ca2+ levels were normal in hearts of Mcu-deleted mice, and mitochondria lacking MCU eventually loaded with Ca2+ 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 Ca2+ loading underlying a"fight-or-flight" response that acutely matches cardiac workload with ATP production.
AB - In the heart, augmented Ca2+ fluxing drives contractility and ATP generation through mitochondrial Ca2+ loading. Pathologic mitochondrial Ca2+ overload with ischemic injury triggers mitochondrial permeability transition pore (MPTP) opening and cardiomyocyte death. Mitochondrial Ca2+ uptake is primarily mediated by the mitochondrial Ca2+ uniporter (MCU). Here, we generated mice with adult and cardiomyocyte-specific deletion of Mcu, which produced mitochondria refractory to acute Ca2+ uptake, with impaired ATP production, and inhibited MPTP opening upon acute Ca2+ challenge. Mice lacking Mcu inthe adult heart were also protected from acute ischemia-reperfusion injury. However, resting/basal mitochondrial Ca2+ levels were normal in hearts of Mcu-deleted mice, and mitochondria lacking MCU eventually loaded with Ca2+ 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 Ca2+ loading underlying a"fight-or-flight" response that acutely matches cardiac workload with ATP production.
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UR - http://www.scopus.com/inward/citedby.url?scp=84937515068&partnerID=8YFLogxK
U2 - 10.1016/j.celrep.2015.06.002
DO - 10.1016/j.celrep.2015.06.002
M3 - Article
C2 - 26119742
AN - SCOPUS:84937515068
VL - 12
SP - 15
EP - 22
JO - Cell Reports
JF - Cell Reports
SN - 2211-1247
IS - 1
ER -