Genetic deletion of the mitochondrial phosphate carrier desensitizes the mitochondrial permeability transition pore and causes cardiomyopathy
Genetic deletion of the mitochondrial phosphate carrier desensitizes the mitochondrial permeability transition pore and causes cardiomyopathy
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DOI：
10.1038/cdd.2014.36
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发表时间：
2014-08-01
影响因子：
12.4
通讯作者：
Molkentin, J. D.
中科院分区：
文献类型：
--
作者：
Kwong, J. Q.;Davis, J.;Molkentin, J. D.
线粒体磷酸盐载体(PIC)是线粒体磷酸盐跨内膜转运的主要途径，对ATP合成起着至关重要的作用。除了在能量产生中的作用外，PIC被认为在细胞死亡中作为线粒体通透性转换孔(MPTP)复合体的组成部分或调节器发挥作用。在这里，我们已经建立了一个具有可诱导的和心脏特异的SLc25a3基因(PIC蛋白)缺失的小鼠模型。Pic蛋白的丢失并没有阻止MPTP的开放，表明它不是这种复合体的直接成孔成分。然而，心脏中SLc25a3的缺失减弱了MPTP对Ca~(2+)挑战的开放，并导致了更大的钙摄取能力。这种由于PIC蛋白丢失或减少而引起的MPTP开放的脱敏可以减轻心肌缺血再灌注损伤，并部分保护培养的细胞免受钙超载诱导的死亡。有趣的是，心脏中SLC25a3基因的长期缺失会导致严重的肥厚，伴随着心室扩张和心脏功能下降，所有这些特征都反映了在SLC25A3基因突变的人类中观察到的心肌病。总之，这些结果表明，尽管PIC不是MPTP的直接成分，但它可以调节其活性，为减少坏死性细胞死亡提供了一个新的治疗靶点。此外，心脏中缺乏SLc25a3的小鼠是一种由线粒体驱动的代谢性心肌病的新模型。
The mitochondrial phosphate carrier (PiC) is critical for ATP synthesis by serving as the primary means for mitochondrial phosphate import across the inner membrane. In addition to its role in energy production, PiC is hypothesized to have a role in cell death as either a component or a regulator of the mitochondrial permeability transition pore (MPTP) complex. Here, we have generated a mouse model with inducible and cardiac-specific deletion of the Slc25a3 gene (PiC protein). Loss of PiC protein did not prevent MPTP opening, suggesting it is not a direct pore-forming component of this complex. However, Slc25a3 deletion in the heart blunted MPTP opening in response to Ca2+ challenge and led to a greater Ca2+ uptake capacity. This desensitization of MPTP opening due to loss or reduction in PiC protein attenuated cardiac ischemic-reperfusion injury, as well as partially protected cells in culture from Ca2+ overload induced death. Intriguingly, deletion of the Slc25a3 gene from the heart long-term resulted in profound hypertrophy with ventricular dilation and depressed cardiac function, all features that reflect the cardiomyopathy observed in humans with mutations in SLC25A3. Together, these results demonstrate that although the PiC is not a direct component of the MPTP, it can regulate its activity, suggesting a novel therapeutic target for reducing necrotic cell death. In addition, mice lacking Slc25a3 in the heart serve as a novel model of metabolic, mitochondrial-driven cardiomyopathy.