Epigenetic regulation of the nuclear-coded GCAT and SHMT2 genes confers human age-associated mitochondrial respiration defects

被引：58

作者：

Hashizume, Osamu ^{[1
]}

Ohnishi, Sakiko ^{[1
]}

Mito, Takayuki ^{[1
]}

Shimizu, Akinori ^{[1
]}

Iashikawa, Kaori ^{[1
]}

Nakada, Kazuto ^{[1
,2
]}

Soda, Manabu ^{[3
]}

Mano, Hiroyuki ^{[3
]}

Togayachi, Sumie ^{[4
]}

Miyoshi, Hiroyuki ^{[4
,5
]}

Okita, Keisuke ^{[6
]}

Hayashi, Jun-ichi ^{[1
,2
,7
]}

机构：

[1] Univ Tsukuba, Fac Life & Environm Sci, Tsukuba, Ibaraki 3058572, Japan

[2] Univ Tsukuba, Int Inst Integrat Sleep Med WPI IIIS, Tsukuba, Ibaraki 3058572, Japan

[3] Univ Tokyo, Grad Sch Med, Dept Cellular Signaling, Bunkyo Ku, Tokyo 1130033, Japan

[4] RIKEN Tsukuba Inst, BioResource Ctr, Subteam Manipulat Cell Fate, Tsukuba, Ibaraki 3050074, Japan

[5] Keio Univ, Sch Med, Dept Physiol, Shinjuku Ku, Tokyo 1608582, Japan

[6] Kyoto Univ, Ctr iPS Cell Res & Applicat, Sakyo Ku, Kyoto 6068507, Japan

[7] Univ Tsukuba, TARA Ctr, Tsukuba, Ibaraki 3058572, Japan

来源：

SCIENTIFIC REPORTS | 2015年 / 5卷

基金：

日本学术振兴会;

关键词：

PLURIPOTENT STEM-CELLS; FUNCTIONAL INTEGRITY; AGING PHENOTYPES; DNA MUTATIONS; COMPLEMENTATION; DYSFUNCTION; MICE;

D O I：

10.1038/srep10434

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Age-associated accumulation of somatic mutations in mitochondrial DNA (mtDNA) has been proposed to be responsible for the age-associated mitochondrial respiration defects found in elderly human subjects. We carried out reprogramming of human fibroblast lines derived from elderly subjects by generating their induced pluripotent stem cells (iPSCs), and examined another possibility, namely that these aging phenotypes are controlled not by mutations but by epigenetic regulation. Here, we show that reprogramming of elderly fibroblasts restores age-associated mitochondrial respiration defects, indicating that these aging phenotypes are reversible and are similar to differentiation phenotypes in that both are controlled by epigenetic regulation, not by mutations in either the nuclear or the mitochondrial genome. Microarray screening revealed that epigenetic downregulation of the nuclear-coded GCAT gene, which is involved in glycine production in mitochondria, is partly responsible for these aging phenotypes. Treatment of elderly fibroblasts with glycine effectively prevented the expression of these aging phenotypes.

引用

页数：10

共 27 条

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