A Pro-Diabetogenic mtDNA Polymorphism in the Mitochondrial-Derived Peptide, MOTS-c

Hirofumi Zempo, et al.

Jul 11, 2019
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Date Received: 23rd May 19

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, Keitaro Tanaka, Pinchas Cohen

Type 2 Diabetes (T2D) is an emerging public health problem in Asia. An Asian 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) showed that males but not females with the C-allele exhibit a higher prevalence of T2D. Furthermore, 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 an exercise, and contributing to the risk of T2D in sedentary males by reducing the activity of MOTS-c.

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This is an abstract of a preprint hosted on an independent third party site. It has not been peer reviewed but is currently under consideration at Nature Communications.

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