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Research Paper|Volume 13, Issue 2|pp 1692—1717

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

Hirofumi Zempo1,3, Su-Jeong Kim2, Noriyuki Fuku1, Yuichiro Nishida4, Yasuki Higaki5, Junxiang Wan2, Kelvin Yen2, Brendan Miller2, Roberto Vicinanza2, Eri Miyamoto-Mikami1, Hiroshi Kumagai1,6, Hisashi Naito1, Jialin Xiao2, Hemal H. Mehta2, Changhan Lee2, Megumi Hara4, Yesha M. Patel7, Veronica W. Setiawan7, Timothy M. Moore8, Andrea L. Hevener8, Yoichi Sutoh9, Atsushi Shimizu9, Kaname Kojima10, Kengo Kinoshita10, Yasumichi Arai11, Nobuyoshi Hirose11, Seiji Maeda12, Keitaro Tanaka4, Pinchas Cohen2
  • 1Graduate School of Health and Sports Science, Juntendo University, Chiba, Japan
  • 2Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA 90089, USA
  • 3Department of Administrative Nutrition, Faculty of Health and Nutrition, Tokyo Seiei College, Tokyo, Japan
  • 4Department of Preventive Medicine, Faculty of Medicine, Saga University, Saga, Japan
  • 5Faculty of Sports and Health Science, Fukuoka University, Fukuoka, Japan
  • 6Japan Society for the Promotion of Science, Tokyo, Japan
  • 7Department of Preventive Medicine, Keck School of Medicine of University of Southern California, Los Angeles, CA 90033, USA
  • 8Division of Endocrinology, Diabetes and Hypertension, Department of Medicine and the Iris Cantor-UCLA Women's Health Research Center at the David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA
  • 9Division of Biomedical Information Analysis, Iwate Tohoku Medical Megabank Organization, Disaster Reconstruction Center, Iwate Medical University, Iwate, Japan
  • 10Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University, Miyagi, Japan
  • 11Center for Supercentenarian Medical Research, Keio University School of Medicine, Tokyo, Japan
  • 12Faculty of Health and Sport Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan
* Co-first authors
# Share senior authorship
Received: November 9, 2020Accepted: December 29, 2020Published: January 19, 2021

Copyright: © 2021 Zempo et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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.