2. Academic Validation
  3. A pro-diabetogenic mtDNA polymorphism in the mitochondrial-derived peptide, MOTS-c

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

  • Aging (Albany NY). 2021 Jan 19;13(2):1692-1717. doi: 10.18632/aging.202529.
Hirofumi Zempo 1 2,  Su-Jeong Kim 3,  Noriyuki Fuku 1,  Yuichiro Nishida 4,  Yasuki Higaki 5,  Junxiang Wan 3,  Kelvin Yen 3,  Brendan Miller 3,  Roberto Vicinanza 3,  Eri Miyamoto-Mikami 1,  Hiroshi Kumagai 1 6,  Hisashi Naito 1,  Jialin Xiao 3,  Hemal H Mehta 3,  Changhan Lee 3,  Megumi Hara 4,  Yesha M Patel 7,  Veronica W Setiawan 7,  Timothy M Moore 8,  Andrea L Hevener 8,  Yoichi Sutoh 9,  Atsushi Shimizu 9,  Kaname Kojima 10,  Kengo Kinoshita 10,  Yasumichi Arai 11,  Nobuyoshi Hirose 11,  Seiji Maeda 12,  Keitaro Tanaka 4,  Pinchas Cohen 3
Affiliations

Affiliations

  • 1 Graduate School of Health and Sports Science, Juntendo University, Chiba, Japan.
  • 2 Department of Administrative Nutrition, Faculty of Health and Nutrition, Tokyo Seiei College, Tokyo, Japan.
  • 3 Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA 90089, USA.
  • 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.
PMID: 33468709 DOI: 10.18632/aging.202529
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.

Keywords

MOTS-c; diabetes; insulin resistance; mitochondrial DNA; polymorphism.

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