Glyceraldehyde 3-phosphate dehydrogenase-S, a sperm-specific glycolytic enzyme, is required for sperm motility and male fertility
Glyceraldehyde 3-phosphate dehydrogenase-S, a sperm-specific glycolytic enzyme, is required for sperm motility and male fertility
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DOI：
10.1073/pnas.0407708101
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发表时间：
2004-11-23
影响因子：
11.1
通讯作者：
O'Brien, DA
中科院分区：
文献类型：
--
作者：
Miki, K;Qu, WD;O'Brien, DA
尽管糖酵解是高度保守的，但值得注意的是，在哺乳动物精子中发现了几个独特的糖酵解同工酶。甘油醛3-磷酸脱氢酶（GAPDS）是一种仅在精子发生时表达的小鼠基因的产物，与其人类同源基因（GAPD2）一样，是精子中唯一的GAPDH同工酶。它与纤维鞘紧密结合，纤维鞘是一种细胞骨架结构，延伸了精子鞭毛的大部分长度。我们通过基因靶向破坏Gapds的表达，选择性地阻断精子糖酵解，并评估其对体内精子功能的相对重要性。Gapds（-/-）男性不育，精子运动严重缺陷，表现为运动迟缓，无向前进展。尽管线粒体耗氧量不变，Gapds（-/-）小鼠精子的ATP水平仅为WT小鼠精子的10.4%。这些结果表明，精子运动所需的大部分能量是由糖酵解而不是氧化磷酸化产生的。此外，糖酵解在精子中的关键作用及其对这种精子特异性酶的依赖表明，GAPDS是一个潜在的避孕靶点，突变或环境因素破坏其活性可能导致男性不育。
Although glycolysis is highly conserved, it is remarkable that several unique isozymes in this central metabolic pathway are found in mammalian sperm. Glyceraldehyde 3-phosphate dehydrogenase-S (GAPDS) is the product of a mouse gene expressed only during spermatogenesis and, like its human ortholog (GAPD2), is the sole GAPDH isozyme in sperm. It is tightly bound to the fibrous sheath, a cytoskeletal structure that extends most of the length of the sperm flagellum. We disrupted Gapds expression by gene targeting to selectively block sperm glycolysis and assess its relative importance for in vivo sperm function. Gapds(-/-) males were infertile and had profound defects in sperm motility, exhibiting sluggish movement without forward progression. Although mitochondrial oxygen consumption was unchanged, sperm from Gapds(-/-) mice had ATP levels that were only 10.4% of those in sperm from WT mice. These results imply that most of the energy required for sperm motility is generated by glycolysis rather than oxidative phosphorylation. Furthermore, the critical role of glycolysis in sperm and its dependence on this sperm-specific enzyme suggest that GAPDS is a potential contraceptive target, and that mutations or environmental agents that disrupt its activity could lead to male infertility.