Cyclophilin D controls mitochondrial pore-dependent Ca2+ exchange, metabolic flexibility, and propensity for heart failure in mice
Cyclophilin D controls mitochondrial pore-dependent Ca2+ exchange, metabolic flexibility, and propensity for heart failure in mice
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DOI：
10.1172/jci43171
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发表时间：
2010-10-01
影响因子：
15.9
通讯作者：
Molkentin, Jeffery D.
中科院分区：
文献类型：
--
作者：
Elrod, John W.;Wong, Renee;Molkentin, Jeffery D.
亲环素D（其由Ppif基因编码）是已知调节线粒体渗透性转换孔（MPTP）的开放的线粒体基质肽基-脯氨酰异构酶。除了调节坏死细胞死亡外，MPTP的生理功能在很大程度上是未知的。在这里，我们已经表明，Ppif（-/-）小鼠表现出显着更大的心脏肥大，纤维化，并在心肌功能的减少，以响应压力超负荷刺激比对照组小鼠。此外，Ppif（-/-）小鼠表现出更大的肥大和肺水肿以及对持续运动刺激的反应降低的存活率。在Ppif（-/-）小鼠中亲环素D的心肌细胞特异性转基因表达挽救了压力超负荷刺激后增强的肥大、心功能降低和心力衰竭的快速发作。从机制上讲，Ppif（-/-）小鼠心脏中的适应不良表型表型与MPTP介导的Ca 2+流出的改变相关，导致线粒体基质Ca 2+水平升高和Ca 2+依赖性磷酸酶的激活增强。基质Ca 2+升高导致葡萄糖氧化相对于脂肪酸增加，从而限制了心脏的代谢灵活性，这在压力期间至关重要地参与补偿。这些结果表明，MPTP保持稳态线粒体Ca 2+水平，以匹配代谢与心肌工作负荷的变化，从而表明MPTP的生理功能。
Cyclophilin D (which is encoded by the Ppif gene) is a mitochondrial matrix peptidyl-prolyl isomerase known to modulate opening of the mitochondrial permeability transition pore (MPTP). Apart from regulating necrotic cell death, the physiologic function of the MPTP is largely unknown. Here we have shown that Ppif(-/-) mice exhibit substantially greater cardiac hypertrophy, fibrosis, and reduction in myocardial function in response to pressure overload stimulation than control mice. In addition, Ppif(-/-) mice showed greater hypertrophy and lung edema as well as reduced survival in response to sustained exercise stimulation. Cardiomyocyte-specific transgene expression of cyclophilin D in Ppif(-/-) mice rescued the enhanced hypertrophy, reduction in cardiac function, and rapid onset of heart failure following pressure overload stimulation. Mechanistically, the mal-adaptive phenotype phenotype in the hearts of Ppif(-/-) mice was associated with an alteration in MPTP-mediated Ca2+ efflux resulting in elevated levels of mitochondrial matrix Ca2+ and enhanced activation of Ca2+-dependent dehydrogenases. Elevated matrix Ca2+ led to increased glucose oxidation relative to fatty acids, thereby limiting the metabolic flexibility of the heart that is critically involved in compensation during stress. These findings suggest that the MPTP maintains homeostatic mitochondrial Ca2+ levels to match metabolism with alterations in myocardial workload, thereby suggesting a physiologic function for the MPTP.