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

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 Naıto; Jialin Xiao; Hemal H. Mehta; Changhan David Lee; Megumi Hara; Yesha M. Patel; Veronica Wendy Setiawan; Timothy M. Moore; Andrea Lynn Hevener; Yoichi Sut­oh; Atsushi Shimizu; Kaname Kojima; Kengo Kinoshita; Yasumichi Arai; Nobuyoshi Hirose; Seiji Maeda; Keitaro Tanaka; Pinchas Cohen

doi:10.18632/aging.202529

GeneticsAgingJan 19, 2021

Peer-reviewed journal article

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

Hirofumi Zempo iD, Su‐Jeong Kim iD, Noriyuki Fuku iD, Yuichiro Nishida iD, Yasuki Higaki iD, Junxiang Wan iD, Kelvin Yen iD, Brendan Miller iD, Roberto Vicinanza iD, Eri Miyamoto‐Mikami iD, Hiroshi Kumagai iD, Hisashi Naıto iD, Jialin Xiao, Hemal H. Mehta iD, Changhan David Lee iD, Megumi Hara iD, Yesha M. Patel iD, Veronica Wendy Setiawan iD, Timothy M. Moore iD, Andrea Lynn Hevener iD, Yoichi Sutoh iD, Atsushi Shimizu iD, Kaname Kojima iD, Kengo Kinoshita iD, Yasumichi Arai iD, , Pinchas Cohen iD

Abstract

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 exercise, and contributing to the risk of T2D in sedentary males by reducing the activity of MOTS-c.

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