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

Sci Rep. 2018 Jan 11;8(1):425. doi: 10.1038/s41598-017-18828-3.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetyltransferases / deficiency
  • Acetyltransferases / genetics
  • Aging, Premature / genetics*
  • Animals
  • Cells, Cultured
  • Embryonic Development
  • Epigenesis, Genetic*
  • Female
  • Fibroblasts / cytology
  • Fibroblasts / metabolism
  • Gene Knockout Techniques
  • Genes, Lethal*
  • Glycine Hydroxymethyltransferase / deficiency
  • Glycine Hydroxymethyltransferase / genetics*
  • Humans
  • Male
  • Mice
  • Mitochondria / genetics
  • Mitochondria / physiology*
  • Models, Animal
  • N-Formylmethionine / metabolism
  • RNA, Transfer / genetics

Substances

  • N-Formylmethionine
  • RNA, Transfer
  • Glycine Hydroxymethyltransferase
  • SHMT protein, human
  • Acetyltransferases