Oppong Abel, Leung Yat Hei, Ghosh Anindya, Peyot Marie-Line, Paquet Marilène, Morales Carlos, Clarke Hugh J, Al-Mulla Fahd, Boyer Alexandre, Madiraju S R Murthy, Boerboom Derek, O'Flaherty Cristian, Prentki Marc
Departments of Nutrition, Biochemistry and Molecular Medicine, University of Montreal, and Montreal Diabetes Research Center, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, QC, Canada.
Centre de recherche en reproduction et fertilité (CRRF), Université de Montréal, Saint-Hyacinthe, Québec, Canada.
Mol Metab. 2024 Dec;90:102063. doi: 10.1016/j.molmet.2024.102063. Epub 2024 Nov 13.
Obesity, diabetes and high-calorie diets are associated with defective sperm function and lowered male fertility. Mature spermatozoa primarily use fructose and glucose, and glucose and glycerol metabolism are important for sperm function. We recently discovered a novel mammalian enzyme, glycerol-3-phosphate (Gro3P) phosphatase (G3PP), and showed that it operates the glycerol shunt by hydrolyzing Gro3P to glycerol, and regulates glucose, lipid and energy metabolism in pancreatic β-cells and liver. We now observed that G3PP expression is the highest in the testis and spermatozoa, and investigated its role in male fertility.
We examined G3PP expression during spermatogenesis in mouse and assessed male fertility and spermatozoon function in conditional germ cell specific G3PP-KO (cG3PP-KO) mice and tamoxifen-inducible conditional germ cell G3PP-KO (icG3PP-KO) mice. We also determined the structural and metabolic parameters and oxidative stress in the spermatozoa from icG3PP-KO and control mice.
G3PP expression in mouse spermatocytes and spermatids markedly increases during spermatogenesis. Male cG3PP-KO mice, in which germ cell G3PP is deleted from embryonic stage, are infertile due to dysfunctional sperm with reduced motility and capacitation, and elevated spontaneous acrosomal reaction and oxidative stress. However, icG3PP-KO male mice do not have altered fertility, due to the presence of ∼10% normal spermatozoa. icG3PP-KO spermatozoa display significantly reduced functionality and morphological and ultrastructural alterations. The icG3PP-KO spermatozoa show reduced glycerol production, elevated levels of Gro3P and reactive oxygen species (ROS), and oxidative stress that is associated with increased mitochondrial membrane potential.
Germ cell G3PP deletion leads to the generation of spermatozoa that are functionally and structurally abnormal, likely due to the build-up of Gro3P that increases mitochondrial membrane potential, ROS, and oxidative stress and alters spermatozoa function. Overall, the results indicate that G3PP and the glycerol shunt are essential for normal spermatozoa function and male fertility.
肥胖、糖尿病和高热量饮食与精子功能缺陷及男性生育力降低有关。成熟精子主要利用果糖和葡萄糖，葡萄糖和甘油代谢对精子功能很重要。我们最近发现了一种新型哺乳动物酶，甘油-3-磷酸（Gro3P）磷酸酶（G3PP），并表明它通过将Gro3P水解为甘油来运作甘油分流，并调节胰腺β细胞和肝脏中的葡萄糖、脂质和能量代谢。我们现在观察到G3PP在睾丸和精子中的表达最高，并研究了其在男性生育中的作用。
我们检测了小鼠精子发生过程中G3PP的表达，并评估了条件性生殖细胞特异性G3PP基因敲除（cG3PP-KO）小鼠和他莫昔芬诱导的条件性生殖细胞G3PP基因敲除（icG3PP-KO）小鼠的雄性生育力和精子功能。我们还测定了icG3PP-KO小鼠和对照小鼠精子的结构和代谢参数以及氧化应激。
在精子发生过程中，小鼠精母细胞和精子细胞中G3PP的表达显著增加。雄性cG3PP-KO小鼠从胚胎期开始生殖细胞G3PP被敲除，由于精子功能障碍，运动能力和获能降低，自发顶体反应和氧化应激升高，导致不育。然而，icG3PP-KO雄性小鼠由于存在约10%的正常精子，生育力没有改变。icG3PP-KO精子的功能显著降低，形态和超微结构发生改变。icG3PP-KO精子甘油生成减少，Gro3P和活性氧（ROS）水平升高，氧化应激与线粒体膜电位升高有关。
生殖细胞G3PP缺失导致精子在功能和结构上异常，可能是由于Gro3P积累增加了线粒体膜电位、ROS和氧化应激，从而改变了精子功能。总体而言，结果表明G3PP和甘油分流对正常精子功能和男性生育至关重要。
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