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

Zempo, H.; Kim, S.-J.; Fuku, N.; Nishida, Y.; Higaki, Y.; Wan, J.; Yen, K.; Miller, B.; Vicinanza, R.; Miyamoto-Mikami, E.; Kumagai, H.; Naito, H.; Xiao, J.; Mehta, H. H.; Lee, C.; Hara, M.; Patel, Y. M.; Setiawan, V. W.; Moore, T. M.; Hevener, A. L.; Sutoh, Y.; Shimizu, A.; Kojima, K.; Kinoshita, K.; Tanaka, K.; Cohen, P.

doi:10.1101/695585

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bioRxiv · 10.1101/695585

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

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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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Zempo, H., Kim, S.-J., Fuku, N., Nishida, Y., Higaki, Y., Wan, J., Yen, K., Miller, B., Vicinanza, R., Miyamoto-Mikami, E., Kumagai, H., Naito, H., Xiao, J., Mehta, H. H., Lee, C., Hara, M., Patel, Y. M., Setiawan, V. W., Moore, T. M., Hevener, A. L., Sutoh, Y., Shimizu, A., Kojima, K., Kinoshita, K., Tanaka, K., Cohen, P.. 2019-07-09. A Pro-Diabetogenic mtDNA Polymorphism in the Mitochondrial-Derived Peptide, MOTS-c. https://doi.org/10.1101/695585

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