MPC1-like Is a Placental Mammal-specific Mitochondrial Pyruvate Carrier Subunit Expressed in Postmeiotic Male Germ Cells*
MPC1-like Is a Placental Mammal-specific Mitochondrial Pyruvate Carrier Subunit Expressed in Postmeiotic Male Germ Cells*
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DOI：
10.1074/jbc.m116.733840
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发表时间：
2016-06
期刊：
影响因子：
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通讯作者：
Benoît Vanderperre;K. Cermakova;J. Escoffier;M. Kaba;Tom Bender;S. Nef;J. Martinou
中科院分区：
文献类型：
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作者：
Benoît Vanderperre;K. Cermakova;J. Escoffier;M. Kaba;Tom Bender;S. Nef;J. Martinou
线粒体丙酮酸载体(MPC)选择性地跨线粒体内膜转运丙酮酸是连接胞质代谢和线粒体代谢的基本步骤。最近对MPC复合体的分子鉴定揭示了两个相互作用的亚基，MPC1和MPC2。虽然在酵母中，一个额外的亚基MPC3可以在功能上取代MPC2，但在高等真核生物中还没有描述替代的MPC亚基。在这里，我们首次报道了一种新的MPC亚单位的存在，称为MPC1样亚单位(MPC1L)，它是胎盘哺乳动物中独有的。MPC1L与MPC1具有较高的序列、结构和拓扑同源性。此外，我们提供了几条证据表明MPC1L在功能上等同于MPC1：1)当MPC2与MPC2共表达时，它在MPC缺失的酵母菌株中挽救丙酮酸的导入；2)在哺乳动物细胞中，它可以与MPC2结合形成功能载体，通过生物发光共振能量转移来评估；3)在MPC1缺失的小鼠胚胎成纤维细胞中，MPC1L挽救丙酮酸驱动的呼吸并稳定MPC2的表达；以及4)MPC1和MPC1L介导的丙酮酸导入显示出类似的效果。然而，我们发现MPC1L具有高度特异性的表达模式，并且几乎仅定位于睾丸，更特异地定位于减数分裂后的精子细胞和精子细胞。这与MPC1/MPC2形成鲜明对比，MPC1/MPC2在整个生物体中普遍表达。到目前为止，这种替代的MPC复合体在胎盘哺乳动物精子发生过程中的生物学重要性尚不清楚。然而，这些发现为研究MPC复合体内的结构-功能关系开辟了新的途径。
Selective transport of pyruvate across the inner mitochondrial membrane by the mitochondrial pyruvate carrier (MPC) is a fundamental step that couples cytosolic and mitochondrial metabolism. The recent molecular identification of the MPC complex has revealed two interacting subunits, MPC1 and MPC2. Although in yeast, an additional subunit, MPC3, can functionally replace MPC2, no alternative MPC subunits have been described in higher eukaryotes. Here, we report for the first time the existence of a novel MPC subunit termed MPC1-like (MPC1L), which is present uniquely in placental mammals. MPC1L shares high sequence, structural, and topological homology with MPC1. In addition, we provide several lines of evidence to show that MPC1L is functionally equivalent to MPC1: 1) when co-expressed with MPC2, it rescues pyruvate import in a MPC-deleted yeast strain; 2) in mammalian cells, it can associate with MPC2 to form a functional carrier as assessed by bioluminescence resonance energy transfer; 3) in MPC1 depleted mouse embryonic fibroblasts, MPC1L rescues the loss of pyruvate-driven respiration and stabilizes MPC2 expression; and 4) MPC1- and MPC1L-mediated pyruvate imports show similar efficiency. However, we show that MPC1L has a highly specific expression pattern and is localized almost exclusively in testis and more specifically in postmeiotic spermatids and sperm cells. This is in marked contrast to MPC1/MPC2, which are ubiquitously expressed throughout the organism. To date, the biological importance of this alternative MPC complex during spermatogenesis in placental mammals remains unknown. Nevertheless, these findings open up new avenues for investigating the structure-function relationship within the MPC complex.