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

• Tani, Haruna

• Ohnishi, Sakiko

• Shitara, Hiroshi

• Mito, Takayuki

• Yamaguchi, Midori

• Yonekawa, Hiromichi

• Hashizume, Osamu

• ISHIKAWA, Kaori

• NAKADA, Kazuto

• Hayashi, Jun-Ichi

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 .

Journal

• Scientific Reports

  Scientific Reports 8 425-, 2018-01

  Nature Publishing Group

Keywords

• Multidisciplinary

Details

• CRID: 1050001202548784896
• NII Article ID: 120007134501
• DOI: 10.1038/s41598-017-18828-3
• ISSN: 20452322
• HANDLE: 2241/00150985
• Web Site: https://tsukuba.repo.nii.ac.jp/records/45703
• Web Site: https://www.nature.com/articles/s41598-017-18828-3.pdf
• Web Site: https://www.nature.com/articles/s41598-017-18828-3
• Text Lang: en
• Article Type: journal article
• Data Source:
  • IRDB
  • Crossref
  • CiNii Articles
  • KAKEN