Graduate School of Life and Environmental Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8572, Japan.
Japan Society for the Promotion of Science (JSPS), 8 Ichiban-cho, Chiyoda-ku, Tokyo, 102-8472, Japan.
Sci Rep. 2019 Nov 5;9(1):16054. doi: 10.1038/s41598-019-52372-6.
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.
在之前的一项研究中，我们提出老年人中观察到的与年龄相关的线粒体呼吸缺陷部分归因于核编码基因的年龄相关下调，包括丝氨酸羟甲基转移酶 2 (SHMT2)，它参与线粒体一碳 (1C) 代谢。这一说法得到了以下证据的支持：即敲除小鼠 Shmt2 会导致源自 Shmt2 敲除 E13.5 胚胎的小鼠胚胎成纤维细胞中的线粒体呼吸缺陷，这些胚胎经历贫血和致死。在这里，我们使用 Shmt2 敲除的 E13.5 胚胎阐明了该基因破坏诱导线粒体呼吸缺陷和胚胎贫血的潜在机制。Shmt2 敲除的 E13.5 胚胎的肝脏而不是大脑表现出线粒体呼吸缺陷和生长迟缓。代谢组学分析显示，Shmt2 缺乏导致胎儿肝脏中 1C 代谢途径的特异性下调，这些途径分别产生牛磺酸和核苷酸，分别为线粒体呼吸功能和细胞分裂提供所需的物质，从而导致线粒体呼吸缺陷和生长迟缓。鉴于胎儿肝脏在小鼠胚胎中负责产生红细胞，胎儿肝脏的生长迟缓直接导致红细胞的耗竭。相比之下，由于红细胞分化的抑制，胎儿肝脏中的线粒体呼吸缺陷也导致了红细胞的耗竭，从而导致 Shmt2 敲除的 E13.5 胚胎发生贫血。
