Disruption of the mouse Shmt2 gene confers embryonic anaemia via foetal liver-specific metabolomic disorders

• Published in: Scientific reports Vol. 9; no. 1; pp. 16054 - 11
• Main Authors: Tani, Haruna, Mito, Takayuki, Velagapudi, Vidya, Ishikawa, Kaori, Umehara, Moe, Nakada, Kazuto, Suomalainen, Anu, Hayashi, Jun-Ichi
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 05.11.2019; Nature Publishing Group
• Subjects: 101/1; 13/31; 631/443/319/333; 631/80/642/333/1465; 64/60; Age; Anemia; Anemia - embryology; Anemia - genetics; Anemia - pathology; Animals; Cell division; Defects; Electron transport; Embryo fibroblasts; Embryos; Erythroblasts; Fetal Diseases - genetics; Fetal Diseases - metabolism; Fetal Diseases - pathology; Fetus - embryology; Fetus - pathology; Gene Knockout Techniques; Geriatrics; Growth rate; Humanities and Social Sciences; Hydroxymethyl and Formyl Transferases - deficiency; Hydroxymethyl and Formyl Transferases - metabolism; Lethality; Liver diseases; Liver Diseases - embryology; Liver Diseases - genetics; Liver Diseases - pathology; Metabolic Diseases - embryology; Metabolic Diseases - genetics; Metabolic Diseases - pathology; Metabolic pathways; Metabolomics; Mice; Mice, Knockout; Mitochondria; Mitochondria, Liver - genetics; Mitochondria, Liver - metabolism; Mitochondria, Liver - pathology; multidisciplinary; Nucleotides; Respiration; Respiratory function; Rodents; Science; Science (multidisciplinary); Serine; Taurine
• ISSN: 2045-2322; 2045-2322
• 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 Shmt 2-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 Shmt 2-knockout E13.5 embryos.