Disruption of the mouse Shmt2 gene confers embryonic anaemia via foetal liver-specific metabolomic disorders
Disruption of the mouse Shmt2 gene confers embryonic anaemia via foetal liver-specific metabolomic disorders
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DOI：
10.1038/s41598-019-52372-6
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发表时间：
2019-11-05
影响因子：
4.6
通讯作者：
Hayashi, Jun-Ichi
中科院分区：
文献类型：
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作者：
Tani, Haruna;Mito, Takayuki;Hayashi, Jun-Ichi
在先前的研究中，我们提出在老年受试者中观察到的与年龄相关的线粒体呼吸缺陷部分是由于与年龄相关的核编码基因的下调，包括丝氨酸羟甲基转移酶2（SHMT2），其参与线粒体一碳（1C）代谢。这一论断得到以下证据的支持：小鼠Shmt 2的破坏诱导小鼠胚胎成纤维细胞中的线粒体呼吸缺陷，所述小鼠胚胎成纤维细胞由经历贫血和致死性的Shmt 2敲除E13.5胚胎产生。在这里，我们阐明了潜在的机制，该基因的破坏诱导线粒体呼吸缺陷和胚胎贫血使用Shmt2基因敲除E13.5胚胎。Shmt2基因敲除E13.5胚胎的肝脏而不是大脑呈现线粒体呼吸缺陷和生长迟缓。代谢组学分析显示，Shmt2缺陷诱导胎儿肝脏特异性下调1C代谢途径，分别产生线粒体呼吸功能和细胞分裂所需的牛磺酸和核苷酸，导致线粒体呼吸缺陷和生长迟缓的表现。考虑到胎肝在小鼠胚胎中产生成红细胞的功能，胎肝生长迟缓直接诱导成红细胞耗竭。相比之下，胎儿肝脏中的线粒体呼吸缺陷也诱导了成红细胞的耗竭，这是由于成红细胞分化的抑制，导致Shmt2基因敲除E13.5胚胎出现贫血。
In a previous study, we proposed that age-related mitochondrial respiration defects observed in elderly subjects are partially due to age-associated downregulation of nuclear-encoded genes, including serine hydroxymethyltransferase 2 (SHMT2), which is involved in mitochondrial one-carbon (1C) metabolism. This assertion is supported by evidence that the disruption of mouse Shmt2 induces mitochondrial respiration defects in mouse embryonic fibroblasts generated from Shmt2-knockout E13.5 embryos experiencing anaemia and lethality. Here, we elucidated the potential mechanisms by which the disruption of this gene induces mitochondrial respiration defects and embryonic anaemia using Shmt2-knockout E13.5 embryos. The livers but not the brains of Shmt2-knockout E13.5 embryos presented mitochondrial respiration defects and growth retardation. Metabolomic profiling revealed that Shmt2 deficiency induced foetal liver-specific downregulation of 1C-metabolic pathways that create taurine and nucleotides required for mitochondrial respiratory function and cell division, respectively, resulting in the manifestation of mitochondrial respiration defects and growth retardation. Given that foetal livers function to produce erythroblasts in mouse embryos, growth retardation in foetal livers directly induced depletion of erythroblasts. By contrast, mitochondrial respiration defects in foetal livers also induced depletion of erythroblasts as a consequence of the inhibition of erythroblast differentiation, resulting in the manifestation of anaemia in Shmt2-knockout E13.5 embryos.