A pro-diabetogenic mtDNA polymorphism in the mitochondrial-derived peptide, MOTS-c.
A pro-diabetogenic mtDNA polymorphism in the mitochondrial-derived peptide, MOTS-c.
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DOI：
10.18632/aging.202529
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发表时间：
2021-01-19
期刊：
影响因子：
--
通讯作者：
Cohen P
中科院分区：
文献类型：
--
作者：
Zempo H;Kim SJ;Fuku N;Nishida Y;Higaki Y;Wan J;Yen K;Miller B;Vicinanza R;Miyamoto-Mikami E;Kumagai H;Naito H;Xiao J;Mehta HH;Lee C;Hara M;Patel YM;Setiawan VW;Moore TM;Hevener AL;Sutoh Y;Shimizu A;Kojima K;Kinoshita K;Arai Y;Hirose N;Maeda S;Tanaka K;Cohen P
2型糖尿病（T2D）是亚洲新兴的公共卫生问题。虽然种族特异性mtDNA多态性已被证明与T2D风险有关，但mtDNA多态性的功能影响和线粒体衍生肽对mtDNA多态性的治疗潜力尚未得到充分探索。在这里，我们发现亚洲特异性线粒体DNA变异m.1382A b> C （rs111033358）导致胰岛素致敏线粒体来源肽MOTS-c中的K14Q氨基酸替换。对三个队列（n = 27,527, J-MICC， MEC和TMM）的荟萃分析显示，携带c等位基因的男性而非女性表现出更高的T2D患病率。在J-MICC中，只有体育活动最低分位数的c等位基因的男性增加了T2D的患病率，这表明运动-基因组相互作用。注射了MOTS-c的高脂肪喂养的雄性小鼠体重减轻，葡萄糖耐量提高，而K14Q-MOTS-c治疗的小鼠则没有。和人类的数据一样，雌性老鼠没有受到影响。在机制上，K14Q-MOTS-c导致体外胰岛素增敏性降低。因此，m.1382A >c多态性与男性对T2D的易感性有关，可能与运动相互作用，并通过降低MOTS-c的活性来增加久坐男性患T2D的风险。
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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影响因子：
4.7
作者：
Hara M;Higaki Y;Imaizumi T;Taguchi N;Nakamura K;Nanri H;Sakamoto T;Horita M;Shinchi K;Tanaka K
通讯作者：
Tanaka K
线粒体DNA多态性的鉴定会改变线粒体基质pH和细胞内钙动力学。
影响因子：
4.5
作者：
Kazuno, An-a;Munakata, Kae;Nagai, Takeharu;Shimozono, Satoshi;Tanaka, Masashi;Yoneda, Makoto;Kato, Nobumasa;Miyawaki, Atsushi;Kato, Tadafumi
通讯作者：
Kato, Tadafumi
影响因子：
4.7
作者：
Kuriyama S;Yaegashi N;Nagami F;Arai T;Kawaguchi Y;Osumi N;Sakaida M;Suzuki Y;Nakayama K;Hashizume H;Tamiya G;Kawame H;Suzuki K;Hozawa A;Nakaya N;Kikuya M;Metoki H;Tsuji I;Fuse N;Kiyomoto H;Sugawara J;Tsuboi A;Egawa S;Ito K;Chida K;Ishii T;Tomita H;Taki Y;Minegishi N;Ishii N;Yasuda J;Igarashi K;Shimizu R;Nagasaki M;Koshiba S;Kinoshita K;Ogishima S;Takai-Igarashi T;Tominaga T;Tanabe O;Ohuchi N;Shimosegawa T;Kure S;Tanaka H;Ito S;Hitomi J;Tanno K;Nakamura M;Ogasawara K;Kobayashi S;Sakata K;Satoh M;Shimizu A;Sasaki M;Endo R;Sobue K;Tohoku Medical Megabank Project Study Group T;Yamamoto M
通讯作者：
Yamamoto M
DOI：
10.18632/aging.100943
发表时间：
2016-04
期刊：
Aging
影响因子：
--
作者：
Cobb LJ;Lee C;Xiao J;Yen K;Wong RG;Nakamura HK;Mehta HH;Gao Q;Ashur C;Huffman DM;Wan J;Muzumdar R;Barzilai N;Cohen P
通讯作者：
Cohen P
影响因子：
--
作者：
Kim SJ;Guerrero N;Wassef G;Xiao J;Mehta HH;Cohen P;Yen K
通讯作者：
Yen K