Compartmentalized metabolism supports midgestation mammalian development.
Compartmentalized metabolism supports midgestation mammalian development.
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DOI：
10.1038/s41586-022-04557-9
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发表时间：
2022-04
期刊：
影响因子：
64.8
通讯作者：
中科院分区：
文献类型：
--
作者：
哺乳动物胚胎发育需要快速生长和适当的代谢调节。随着胎儿器官的发育，中期的特点是氧气和营养的可获得性增加。要了解新陈代谢如何支持发育，需要在子宫内的模型生物中直接观察新陈代谢。在这里，我们使用同位素示踪和代谢组学来确定小鼠中期胎盘和胚胎中不断演变的代谢程序。这些组织在整个中期的代谢都不同，但我们精确地将妊娠天数(GD)10.5-11.5作为胎盘和胚胎的过渡期。同位素示踪显示，不同组织之间的碳水化合物代谢和快速依赖葡萄糖的嘌呤合成存在差异，尤其是在胚胎中。在胚胎中，葡萄糖对三羧酸(TCA)代谢周期的贡献在整个中期都会上升，但在胎盘中不会。到GD12.5，胚胎内明显的分区代谢程序，包括不同器官中对TCA循环的不同营养贡献。为了了解与孟德尔代谢缺陷相关的发育异常，我们分析了LIPT1缺陷的小鼠，LIPT1是一种激活与TCA循环相关的2-酮酸脱氢酶的酶。LIPT1缺乏抑制了GD10.5-GD11.5转换过程中的TCA循环代谢，扰乱了大脑、心脏和红细胞的发育，并导致GD11.5的胚胎死亡。这些数据记录了子宫内发育器官的个体化代谢方案。对小鼠胚胎的代谢组学分析表明，在怀孕10.5天和11.5天之间，代谢向三羧酸循环转变，导致随后开发器官特定的代谢程序。
Mammalian embryogenesis requires rapid growth and proper metabolic regulation. Midgestation features increasing oxygen and nutrient availability concomitant with fetal organ development. Understanding how metabolism supports development requires approaches to observe metabolism directly in model organisms in utero. Here we used isotope tracing and metabolomics to identify evolving metabolic programmes in the placenta and embryo during midgestation in mice. These tissues differ metabolically throughout midgestation, but we pinpointed gestational days (GD) 10.5–11.5 as a transition period for both placenta and embryo. Isotope tracing revealed differences in carbohydrate metabolism between the tissues and rapid glucose-dependent purine synthesis, especially in the embryo. Glucose’s contribution to the tricarboxylic acid (TCA) cycle rises throughout midgestation in the embryo but not in the placenta. By GD12.5, compartmentalized metabolic programmes are apparent within the embryo, including different nutrient contributions to the TCA cycle in different organs. To contextualize developmental anomalies associated with Mendelian metabolic defects, we analysed mice deficient in LIPT1, the enzyme that activates 2-ketoacid dehydrogenases related to the TCA cycle. LIPT1 deficiency suppresses TCA cycle metabolism during the GD10.5–GD11.5 transition, perturbs brain, heart and erythrocyte development and leads to embryonic demise by GD11.5. These data document individualized metabolic programmes in developing organs in utero. Metabolomics analysis of the mouse embryo shows a metabolic shift towards the tricarboxylic acid cycle between gestational days 10.5 and 11.5, leading to the subsequent development of organ-specific metabolic programmes.
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影响因子：
64.8
作者：
Cao, Junyue;Spielmann, Malte;Shendure, Jay
通讯作者：
Shendure, Jay
影响因子：
21.3
作者：
Flores A;Schell J;Krall AS;Jelinek D;Miranda M;Grigorian M;Braas D;White AC;Zhou JL;Graham NA;Graeber T;Seth P;Evseenko D;Coller HA;Rutter J;Christofk HR;Lowry WE
通讯作者：
Lowry WE
影响因子：
3.7
作者：
Beutner G;Eliseev RA;Porter GA Jr
通讯作者：
Porter GA Jr
通过 mTORC1 介导的蛋白质翻译调节红细胞生成过程中的线粒体生物发生。
影响因子：
21.3
作者：
Liu X;Zhang Y;Ni M;Cao H;Signer RAJ;Li D;Li M;Gu Z;Hu Z;Dickerson KE;Weinberg SE;Chandel NS;DeBerardinis RJ;Zhou F;Shao Z;Xu J
通讯作者：
Xu J
影响因子：
8.8
作者：
Ni, Min;Solmonson, Ashley;DeBerardinis, Ralph J.
通讯作者：
DeBerardinis, Ralph J.