Mice deficient in the Shmt2 gene have mitochondrial respiration defects and are embryonic lethal

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ID: 107992
2018
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Abstract
Abstract Accumulation of somatic mutations in mitochondrial DNA (mtDNA) has been proposed to be responsible for human aging and age-associated mitochondrial respiration defects. However, our previous findings suggested an alternative hypothesis of human aging—that epigenetic changes but not mutations regulate age-associated mitochondrial respiration defects, and that epigenetic downregulation of nuclear-coded genes responsible for mitochondrial translation [e.g., glycine C-acetyltransferase (GCAT), serine hydroxymethyltransferase 2 (SHMT2)] is related to age-associated respiration defects. To examine our hypothesis, here we generated mice deficient in Gcat or Shmt2 and investigated whether they have respiration defects and premature aging phenotypes. Gcat-deficient mice showed no macroscopic abnormalities including premature aging phenotypes for up to 9 months after birth. In contrast, Shmt2-deficient mice showed embryonic lethality after 13.5 days post coitum (dpc), and fibroblasts obtained from 12.5-dpc Shmt2-deficient embryos had respiration defects and retardation of cell growth. Because Shmt2 substantially controls production of N-formylmethionine-tRNA (fMet-tRNA) in mitochondria, its suppression would reduce mitochondrial translation, resulting in expression of the respiration defects in fibroblasts from Shmt2-deficient embryos. These findings support our hypothesis that age-associated respiration defects in fibroblasts of elderly humans are caused not by mtDNA mutations but by epigenetic regulation of nuclear genes including SHMT2.
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tani2018micescientific Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Tani, Haruna;Ohnishi, Sakiko;Shitara, Hiroshi;Mito, Takayuki;Yamaguchi, Midori;Yonekawa, Hiromichi;Hashizume, Osamu;Ishikawa, Kaori;Nakada, Kazuto;Hayashi, Jun-Ichi;
Journal Scientific reports
Year 2018
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