The Mitochondrial Calcium Uniporter Matches Energetic Supply with Cardiac Workload during Stress and Modulates Permeability Transition.
The Mitochondrial Calcium Uniporter Matches Energetic Supply with Cardiac Workload during Stress and Modulates Permeability Transition.
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DOI：
10.1016/j.celrep.2015.06.017
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发表时间：
2015-07-07
期刊：
影响因子：
8.8
通讯作者：
Elrod JW
中科院分区：
文献类型：
--
作者：
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
心肌收缩是由细胞内钙（Ca2+）的可变通量介导的，Ca2+被认为通过线粒体钙单转运（MCU）通道整合到线粒体中，以匹配能量需求。在这里，我们研究了成年期缺乏Mcu （Mcu通道的孔隙形成亚基）的条件性心肌细胞特异性突变小鼠。在体内心肌缺血-再灌注损伤模型中，Mcu - / -小鼠没有明显的基线表型，并且通过阻止线粒体通透性过渡孔的激活，减少梗死面积和保持心功能来保护mCa2+-过载。此外，我们发现Mcu - / -小鼠对急性β-肾上腺素能受体刺激缺乏收缩反应，同时无法激活线粒体脱氢酶，并显示出生物能量储备能力降低。这些结果支持的假设，MCU可能是可有可无的稳态心脏功能，但需要调节Ca2+依赖性代谢在急性应激。
Cardiac contractility is mediated by 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 in vivo 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.