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Disruption of the mouse Shmt2 gene confers embryonic anaemia via foetal liver-specific metabolomic disorders.
Scientific Reports ( IF 3.8 ) Pub Date : 2019-11-05 , DOI: 10.1038/s41598-019-52372-6
Haruna Tani 1, 2 , Takayuki Mito 3 , Vidya Velagapudi 4 , Kaori Ishikawa 1, 5 , Moe Umehara 1 , Kazuto Nakada 1, 5 , Anu Suomalainen 3, 6 , Jun-Ichi Hayashi 7
Scientific Reports ( IF 3.8 ) Pub Date : 2019-11-05 , DOI: 10.1038/s41598-019-52372-6
Haruna Tani 1, 2 , Takayuki Mito 3 , Vidya Velagapudi 4 , Kaori Ishikawa 1, 5 , Moe Umehara 1 , Kazuto Nakada 1, 5 , Anu Suomalainen 3, 6 , Jun-Ichi Hayashi 7
Affiliation
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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.
中文翻译：
小鼠Shmt2基因的破坏通过胎儿肝脏特异性代谢组学障碍赋予胚胎性贫血。
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归因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），该基因参与了线粒体一碳（1C ）新陈代谢。有证据表明，对小鼠Shmt2的破坏会在由经历贫血和致死性的Shmt2基因敲除E13.5胚胎产生的小鼠胚胎成纤维细胞中诱导线粒体呼吸缺陷，这一证据得到了支持。在这里，我们阐明了使用Shmt2基因敲除E13.5胚胎破坏该基因诱导线粒体呼吸缺陷和胚胎性贫血的潜在机制。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缺乏症引起胎儿肝脏特异性1C代谢途径下调，从而分别产生牛磺酸和线粒体呼吸功能和细胞分裂所需的核苷酸，从而导致线粒体呼吸缺陷和生长迟缓的表现。考虑到胎儿肝的功能是在小鼠胚胎中产生成红细胞，胎儿肝的生长迟缓直接导致了成红细胞的消耗。相比之下，胎儿肝脏中的线粒体呼吸缺陷也由于抑制成血红细胞分化而导致了成血红细胞的耗竭，从而导致Shmt2基因敲除E13.5胚胎出现贫血。
更新日期：2019-11-06
中文翻译：
小鼠Shmt2基因的破坏通过胎儿肝脏特异性代谢组学障碍赋予胚胎性贫血。
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归因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），该基因参与了线粒体一碳（1C ）新陈代谢。有证据表明，对小鼠Shmt2的破坏会在由经历贫血和致死性的Shmt2基因敲除E13.5胚胎产生的小鼠胚胎成纤维细胞中诱导线粒体呼吸缺陷，这一证据得到了支持。在这里，我们阐明了使用Shmt2基因敲除E13.5胚胎破坏该基因诱导线粒体呼吸缺陷和胚胎性贫血的潜在机制。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缺乏症引起胎儿肝脏特异性1C代谢途径下调，从而分别产生牛磺酸和线粒体呼吸功能和细胞分裂所需的核苷酸，从而导致线粒体呼吸缺陷和生长迟缓的表现。考虑到胎儿肝的功能是在小鼠胚胎中产生成红细胞，胎儿肝的生长迟缓直接导致了成红细胞的消耗。相比之下，胎儿肝脏中的线粒体呼吸缺陷也由于抑制成血红细胞分化而导致了成血红细胞的耗竭，从而导致Shmt2基因敲除E13.5胚胎出现贫血。
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