The Mitochondrial Calcium Uniporter Selectively Matches Metabolic Output to Acute Contractile Stress in the Heart.
The Mitochondrial Calcium Uniporter Selectively Matches Metabolic Output to Acute Contractile Stress in the Heart.
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DOI：
10.1016/j.celrep.2015.06.002
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发表时间：
2015-07-07
期刊：
影响因子：
8.8
通讯作者：
Molkentin JD
中科院分区：
文献类型：
--
作者：
Kwong JQ;Lu X;Correll RN;Schwanekamp JA;Vagnozzi RJ;Sargent MA;York AJ;Zhang J;Bers DM;Molkentin JD
在心脏中，增加的Ca 2+流动通过线粒体Ca 2+负载驱动收缩性和ATP产生。病理性线粒体Ca 2+超载与缺血性损伤触发线粒体通透性转换孔（MPTP）开放和心肌细胞死亡。线粒体Ca 2+摄取主要由线粒体Ca 2+单向转运体（MCU）介导。在这里，我们产生了成年小鼠和心肌细胞特异性删除的Mcu，这产生线粒体难治急性Ca 2+摄取，增强ATP的生产和MPTP开放后，急性Ca 2+的挑战。成年心脏中缺乏Mcu的小鼠也受到保护，免受急性缺血再灌注损伤。然而，静息/基础线粒体Ca 2+水平在Mcu缺失小鼠的心脏中是正常的，并且缺乏MCU的线粒体在应激刺激后最终负载有Ca 2+。事实上，删除了Mcu的小鼠无法立即在跑步机上冲刺，除非热身30分钟。因此，MCU是短期线粒体Ca 2+负载的专用调节剂，其潜在的“战斗或逃跑”反应使心脏工作负荷与ATP产生急剧匹配。
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, augmented ATP production and MPTP opening upon acute Ca2+ challenge. Mice lacking Mcu in the 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 30 minutes. 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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影响因子：
20.1
作者：
Wilkins, BJ;Dai, YS;Molkentin, JD
通讯作者：
Molkentin, JD
影响因子：
12.4
作者：
Kwong, J. Q.;Davis, J.;Molkentin, J. D.
通讯作者：
Molkentin, J. D.
影响因子：
29.4
作者：
GROSKREUTZ, JL;BRONK, SF;GORES, GJ
通讯作者：
GORES, GJ
影响因子：
2.9
作者：
Glancy, Brian;Balaban, Robert S.
通讯作者：
Balaban, Robert S.
DOI：
10.1126/science.1242993
发表时间：
2013-12-13
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Sancak Y;Markhard AL;Kitami T;Kovács-Bogdán E;Kamer KJ;Udeshi ND;Carr SA;Chaudhuri D;Clapham DE;Li AA;Calvo SE;Goldberger O;Mootha VK
通讯作者：
Mootha VK