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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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 -