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

• Published in: Scientific reports Vol. 8; no. 1; p. 425
• Main Authors: Tani, Haruna, Ohnishi, Sakiko, Shitara, Hiroshi, Mito, Takayuki, Yamaguchi, Midori, Yonekawa, Hiromichi, Hashizume, Osamu, Ishikawa, Kaori, Nakada, Kazuto, Hayashi, Jun-Ichi
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 11.01.2018; Nature Publishing Group
• Subjects: 38/23; 631/443/7; 631/80/642/333/1465; 64/110; 82/80; Acetyltransferase; Age; Aging; Defects; Electron transport; Epigenetics; Fibroblasts; Gene regulation; Geriatrics; Glycine C-acetyltransferase; Humanities and Social Sciences; Hypotheses; Lethality; Mitochondrial DNA; multidisciplinary; Mutation; Respiration; Science; Science (multidisciplinary); Serine; Translation; tRNA fMet
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-017-18828-3

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 .