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

Abstract

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.

Impairment of the mitochondrial one-carbon metabolism enzyme SHMT2 causes a novel brain and heart developmental syndrome

“…In previous works, Shmt2 knockout mice exhibited embryonic lethality, attributed to severe mitochondrial respiration defects in fetal liver, and ensuing inhibition of erythroblast differentiation resulting in anemia. Moreover, metabolic defects were not observed in brain tissue, possibly due to the preferential use of the glycine cleavage system to provide one-carbon units [ 17 ]. To investigate whether the patients’ neurological phenotype could be mediated by non-neuronal autonomous mechanisms, we knocked down Shmt2 specifically in Drosophila motor neurons (~ 65% knockdown of Shmt2 RNA as shown previously by qPCR) [ 3 ].…”

SHMT2 reduces fatty liver but is necessary for liver inflammation and fibrosis in mice

“…In mice, whole-body deletion of SHMT2 causes embryonic lethality due to faulty fetal hematopoiesis in embryonic liver 22 , making it impossible to assess adult phenotypes. To address this, we created a floxed SHMT2 mouse allele (SHMT2 fl/fl ) with two loxP sites spanning exons 3–12, allowing for conditional targeting by lox/Cre recombination (Fig.…”

“…The proper oxidation of mitochondria is crucial in disposing of fatty acids and preventing NAFLD. Previous research has indicated that SHMT2 is critical in maintaining electron transport chain (ETC) protein expression and mitochondrial respiration in murine embryonic fibroblasts and human HEK293 cells 22 , 29 – 31 . However, upon studying SHMT2 HKO mice livers under chow-fed conditions, Western blotting analysis revealed that the protein markers for each respiratory complex were expressed at similar levels in comparison to control mice (Fig.…”

Glycyrrhetinic acid restricts mitochondrial energy metabolism by targeting SHMT2

“…The SHMT2 enzyme is usually highly expressed in cancers, and SHMT2 deficiency leads to mitochondrial respiration defects ( Lucas et al., 2018 ; Minton et al., 2018 ; Morscher et al., 2018 ; Tani et al., 2018 , 2019 ), which makes SHMT2 a promising target for cancer treatment ( Ding et al., 2013 ; Kim et al., 2015 ; Liu et al., 2021 ; Nguyen et al., 2021 ; Wei et al., 2018 ; Yang et al., 2018 ). The mitochondrial respiration system is a well-known machine that generates ATP in mammalian cells.…”