Department of Physiology, Development and Neuroscience, Centre for Trophoblast Research, University of Cambridge, Cambridge, UK.
Biol Reprod. 2022 Jun 13;106(6):1292-1311. doi: 10.1093/biolre/ioac056.
Fetal growth depends on placental function, which requires energy from mitochondria. Here we investigated whether mitochondrial function in the placenta relates to the growth of the lightest and heaviest fetuses of each sex within the litter of mice. Placentas from the lightest and heaviest fetuses were taken to evaluate placenta morphology (stereology), mitochondrial energetics (high-resolution respirometry), mitochondrial regulators, nutrient transporters, hormone handling, and signaling pathways (qPCR and Western blotting). We found that mitochondrial complex I and II oxygen consumption rate was greater for placentas supporting the lightest female fetuses, although placental complex I abundance of the lightest females and complexes III and V of the lightest males were decreased compared to their heaviest counterparts. Expression of mitochondrial biogenesis (Nrf1) and fission (Drp1 and Fis1) genes was lower in the placenta from the lightest females, whilst biogenesis-related gene Tfam was greater in the placenta of the lightest male fetuses. In addition, placental morphology and steroidogenic gene (Cyp17a1 and Cyp11a1) expression were aberrant for the lightest females, but glucose transporter (Slc2a1) expression was lower in only the lightest males versus their heaviest counterparts. Differences in intra-litter placental phenotype were related to changes in the expression of hormone-responsive (androgen receptor) and metabolic signaling (AMPK, AKT, and PPARγ) pathways. Thus, in normal mouse pregnancy, placental structure, function, and mitochondrial phenotype are differentially responsive to the growth of the female and male fetus. This study may inform the design of sex-specific therapies for placental insufficiency and fetal growth abnormalities with life-long benefits for the offspring.
胎儿的生长依赖于胎盘的功能，而胎盘的功能需要线粒体提供能量。在这里，我们研究了胎盘的线粒体功能是否与每个窝仔中最轻和最重胎儿的生长有关。从最轻和最重的胎儿中取出胎盘，以评估胎盘形态（体视学）、线粒体能量学（高分辨率呼吸测定）、线粒体调节因子、营养转运体、激素处理和信号通路（qPCR 和 Western blot）。我们发现，支持最轻雌性胎儿的胎盘的线粒体复合物 I 和 II 的耗氧量更大，尽管与最重的对应物相比，最轻雌性的胎盘复合物 I 丰度以及最轻雄性的复合物 III 和 V 降低。线粒体生物发生（Nrf1）和分裂（Drp1 和 Fis1）基因的表达在最轻雌性的胎盘较低，而在最轻雄性胎儿的胎盘中，线粒体生物发生相关基因 Tfam 更高。此外，最轻雌性的胎盘形态和类固醇生成基因（Cyp17a1 和 Cyp11a1）表达异常，但仅在最轻雄性中葡萄糖转运体（Slc2a1）的表达低于其最重的对应物。窝仔内胎盘表型的差异与激素反应（雄激素受体）和代谢信号（AMPK、AKT 和 PPARγ）途径的表达变化有关。因此，在正常的小鼠妊娠中，胎盘的结构、功能和线粒体表型对雌性和雄性胎儿的生长有不同的反应。这项研究可能为胎盘功能不全和胎儿生长异常的性别特异性治疗提供信息，并为后代带来终身受益。
