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A pro-diabetogenic mtDNA polymorphism in the mitochondrial-derived peptide, MOTS-c

発表形態:
原著論文
主要業績:
主要業績
単著・共著:
共著
発表年月:
2021年01月
DOI:
10.18632/aging.202529
会議属性:
指定なし
査読:
有り
リンク情報:

日本語フィールド

著者:
*Hirofumi Zempo, Su-Jeong Kim, Noriyuki Fuku, Yuichiro Nishida, Yasuki Higaki, Junxiang Wan, Kelvin Yen, Brendan Miller, Roberto Vicinanza, Eri Miyamoto-Mikami, Hiroshi Kumagai, Hisashi Naito, Jialin Xiao, Hemal H Mehta, Changhan Lee, Megumi Hara, Yesha M Patel, Veronica W Setiawan, Timothy M Moore, Andrea L Hevener, Yoichi Sutoh, Atsushi Shimizu, Kaname Kojima, Kengo Kinoshita, Yasumichi Arai, Nobuyoshi Hirose, Seiji Maeda, Keitaro Tanaka, Pinchas Cohen
題名:
A pro-diabetogenic mtDNA polymorphism in the mitochondrial-derived peptide, MOTS-c
発表情報:
Aging (Albany NY) 巻: 13 号: 2 ページ: 1692-1717
キーワード:
MOTS-c; diabetes; insulin resistance; mitochondrial DNA; polymorphis
概要:
Type 2 Diabetes (T2D) is an emerging public health problem in Asia. Although ethnic specific mtDNA polymorphisms have been shown to contribute to T2D risk, the functional effects of the mtDNA polymorphisms and the therapeutic potential of mitochondrial-derived peptides at the mtDNA polymorphisms are underexplored. Here, we showed an Asian-specific mitochondrial DNA variation m.1382A>C (rs111033358) leads to a K14Q amino acid replacement in MOTS-c, an insulin sensitizing mitochondrial-derived peptide. Meta-analysis of three cohorts (n = 27,527, J-MICC, MEC, and TMM) show that males but not females with the C-allele exhibit a higher prevalence of T2D. In J-MICC, only males with the C-allele in the lowest tertile of physical activity increased their prevalence of T2D, demonstrating a kinesio-genomic interaction. High-fat fed, male mice injected with MOTS-c showed reduced weight and improved glucose tolerance, but not K14Q-MOTS-c treated mice. Like the human data, female mice were unaffected. Mechanistically, K14Q-MOTS-c leads to diminished insulin-sensitization in vitro. Thus, the m.1382A>C polymorphism is associated with susceptibility to T2D in men, possibly interacting with exercise, and contributing to the risk of T2D in sedentary males by reducing the activity of MOTS-c.
抄録:

英語フィールド

Author:
*Hirofumi Zempo, Su-Jeong Kim, Noriyuki Fuku, Yuichiro Nishida, Yasuki Higaki, Junxiang Wan, Kelvin Yen, Brendan Miller, Roberto Vicinanza, Eri Miyamoto-Mikami, Hiroshi Kumagai, Hisashi Naito, Jialin Xiao, Hemal H Mehta, Changhan Lee, Megumi Hara, Yesha M Patel, Veronica W Setiawan, Timothy M Moore, Andrea L Hevener, Yoichi Sutoh, Atsushi Shimizu, Kaname Kojima, Kengo Kinoshita, Yasumichi Arai, Nobuyoshi Hirose, Seiji Maeda, Keitaro Tanaka, Pinchas Cohen
Title:
A pro-diabetogenic mtDNA polymorphism in the mitochondrial-derived peptide, MOTS-c
Announcement information:
Aging (Albany NY) Vol: 13 Issue: 2 Page: 1692-1717
Keyword:
MOTS-c; diabetes; insulin resistance; mitochondrial DNA; polymorphis
An abstract:
Type 2 Diabetes (T2D) is an emerging public health problem in Asia. Although ethnic specific mtDNA polymorphisms have been shown to contribute to T2D risk, the functional effects of the mtDNA polymorphisms and the therapeutic potential of mitochondrial-derived peptides at the mtDNA polymorphisms are underexplored. Here, we showed an Asian-specific mitochondrial DNA variation m.1382A>C (rs111033358) leads to a K14Q amino acid replacement in MOTS-c, an insulin sensitizing mitochondrial-derived peptide. Meta-analysis of three cohorts (n = 27,527, J-MICC, MEC, and TMM) show that males but not females with the C-allele exhibit a higher prevalence of T2D. In J-MICC, only males with the C-allele in the lowest tertile of physical activity increased their prevalence of T2D, demonstrating a kinesio-genomic interaction. High-fat fed, male mice injected with MOTS-c showed reduced weight and improved glucose tolerance, but not K14Q-MOTS-c treated mice. Like the human data, female mice were unaffected. Mechanistically, K14Q-MOTS-c leads to diminished insulin-sensitization in vitro. Thus, the m.1382A>C polymorphism is associated with susceptibility to T2D in men, possibly interacting with exercise, and contributing to the risk of T2D in sedentary males by reducing the activity of MOTS-c.


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