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.
Highlights
Because mitochondria produce reactive oxygen species endogenously and preferentially accumulate exogenous chemical carcinogens, mitochondrial DNA is exposed to these mutagens, resulting in accumulation of somatic mutations with age[1,2,3,4,5]
Our microarray screening results suggest that epigenetic downregulation of the nuclear genes glycine C-acetyltransferase (GCAT) and serine hydroxymethyltransferase 2 (SHMT2) is involved in age-associated respiration defects of the fibroblasts of elderly humans[12]
We generated knockout mouse strains deficient in the Gcat gene or the Shmt[2] gene by using the CRISPR/Cas[9] system
Summary
Because mitochondria produce reactive oxygen species endogenously and preferentially accumulate exogenous chemical carcinogens, mitochondrial DNA (mtDNA) is exposed to these mutagens, resulting in accumulation of somatic mutations with age[1,2,3,4,5]. Our recent study[12] addressed these issues by deep sequencing analysis of mtDNA and showed that mtDNA in fibroblasts from elderly humans does not accumulate somatic mutations Reprogramming of these fibroblasts by generating induced pluripotent stem cells (iPSCs) restores normal respiratory function[12]. Because the products of both genes are localized in mitochondria and regulate glycine production in mitochondria[13,14], their downregulation would induce defects in mitochondrial translation and respiratory function, resulting in the age-associated respiration defects found in the fibroblasts of elderly humans[6,7] To examine this possibility, we generated mice deficient in Gcat or Shmt[2], and investigated whether these mice would have mitochondrial respiration defects and premature aging phenotypes
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