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, #, ,

  • 1 Graduate School of Health and Sports Science, Juntendo University, Chiba, Japan
  • 2 Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA 90089, USA
  • 3 Department of Administrative Nutrition, Faculty of Health and Nutrition, Tokyo Seiei College, Tokyo, Japan
  • 4 Department of Preventive Medicine, Faculty of Medicine, Saga University, Saga, Japan
  • 5 Faculty of Sports and Health Science, Fukuoka University, Fukuoka, Japan
  • 6 Japan Society for the Promotion of Science, Tokyo, Japan
  • 7 Department of Preventive Medicine, Keck School of Medicine of University of Southern California, Los Angeles, CA 90033, USA
  • 8 Division 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
  • 9 Division of Biomedical Information Analysis, Iwate Tohoku Medical Megabank Organization, Disaster Reconstruction Center, Iwate Medical University, Iwate, Japan
  • 10 Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University, Miyagi, Japan
  • 11 Center for Supercentenarian Medical Research, Keio University School of Medicine, Tokyo, Japan
  • 12 Faculty of Health and Sport Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan
* Co-first authors
# Share senior authorship

Received: November 9, 2020       Accepted: December 29, 2020       Published: January 19, 2021
How to Cite

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.


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.


ANOVA: one-way analysis of variance; BMI: body mass index; DMEM: Dulbecco’s modified Eagle’s medium; GTT: glucose tolerance test; HFD: High fat diet; IP: intraperitoneal; J-MICC: Japan Multi-Institutional Collaborative Cohort; JDS: Japan Diabetes Society; K: Lysine; MDP: mitochondrial derived peptide; MEC: Multiethnic Cohort; MOTS-c: mitochondrial open-reading-frame of the twelve S rRNA –type c; MSD: MESO SCALE DISCOVERY; MVPA: moderate- to vigorous-intensity physical activity; NGSP: National Glyco-hemoglobin Standardization Program; ORF: open reading frames; Q: Glutamine; SNP: Single Nucleotide Polymorphism; T2D: Type 2 Diabetes; TMM: Tohoku Medical Megabank project.