Mice deficient in the Shmt2 gene have mitochondrial respiration defects and are embryonic lethal.
Mice deficient in the Shmt2 gene have mitochondrial respiration defects and are embryonic lethal.
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DOI：
10.1038/s41598-017-18828-3
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发表时间：
2018-01-11
影响因子：
4.6
通讯作者：
Hayashi JI
中科院分区：
文献类型：
--
作者：
Tani H;Ohnishi S;Shitara H;Mito T;Yamaguchi M;Yonekawa H;Hashizume O;Ishikawa K;Nakada K;Hayashi JI
线粒体DNA（mtDNA）体细胞突变的积累被认为是人类衰老以及与年龄相关的线粒体呼吸缺陷的原因。然而，我们之前的研究结果提出了人类衰老的另一种假说——是表观遗传变化而非突变调控与年龄相关的线粒体呼吸缺陷，并且负责线粒体翻译的核编码基因（例如，甘氨酸C - 乙酰转移酶（GCAT）、丝氨酸羟甲基转移酶2（SHMT2））的表观遗传下调与年龄相关的呼吸缺陷有关。为了验证我们的假说，在此我们构建了Gcat或Shmt2缺陷型小鼠，并研究它们是否存在呼吸缺陷和早衰表型。Gcat缺陷型小鼠在出生后长达9个月内未出现包括早衰表型在内的宏观异常。相反，Shmt2缺陷型小鼠在交配后13.5天（dpc）出现胚胎致死，从12.5 - dpc的Shmt2缺陷型胚胎获取的成纤维细胞存在呼吸缺陷和细胞生长迟缓。由于Shmt2在很大程度上控制着线粒体中N - 甲酰甲硫氨酸 - tRNA（fMet - tRNA）的产生，其抑制会减少线粒体翻译，从而导致Shmt2缺陷型胚胎的成纤维细胞出现呼吸缺陷。这些发现支持了我们的假说，即老年人成纤维细胞中与年龄相关的呼吸缺陷不是由mtDNA突变引起的，而是由包括SHMT2在内的核基因的表观遗传调控所致。
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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线粒体DNA突变和衰老：细节中的魔鬼？
影响因子：
11.4
作者：
Khrapko, Konstantin;Vijg, Jan
通讯作者：
Vijg, Jan
影响因子：
29
作者：
Ducker GS;Chen L;Morscher RJ;Ghergurovich JM;Esposito M;Teng X;Kang Y;Rabinowitz JD
通讯作者：
Rabinowitz JD
DOI：
10.1038/nrg1606
发表时间：
2005-05
期刊：
Nature reviews. Genetics
影响因子：
--
作者：
通讯作者：
--
影响因子：
4.8
作者：
Isobe, K;Ito, S;Hayashi, JI
通讯作者：
Hayashi, JI
DOI：
10.1016/j.bbrc.2004.12.105
发表时间：
2005-02-25
影响因子：
3.1
作者：
Akimoto, M;Niikura, M;Hayashi, JI
通讯作者：
Hayashi, JI