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

Summary

Human genetic association study (a meta-analysis of three cohorts) combined with mouse and cell experiments. The authors showed that an Asian-specific mitochondrial DNA variant, m.1382A>C (rs111033358), replaces lysine with glutamine at position 14 (K14Q) of MOTS-c, an insulin-sensitizing mitochondrial-derived peptide. Across the J-MICC, MEC, and TMM cohorts (n = 27,527), men but not women carrying the C-allele had a higher prevalence of type 2 diabetes (T2D). In J-MICC, this was limited to C-allele men in the lowest tertile of physical activity, which the authors describe as a kinesio-genomic interaction.

Key Findings

• m.1382A>C (rs111033358) produces a K14Q amino-acid replacement in the MOTS-c peptide
• Male, but not female, C-allele carriers had a higher prevalence of T2D in the three-cohort meta-analysis
• In J-MICC, higher T2D prevalence appeared only in C-allele men with the lowest physical activity
• In high-fat-fed male mice, injected MOTS-c reduced weight and improved glucose tolerance; K14Q-MOTS-c did not, and female mice were unaffected
• In vitro, K14Q-MOTS-c produced diminished insulin sensitization
• The abstract does not report any association between this variant and longevity

Relevance to MOTS-c

Human genetic evidence that MOTS-c activity matters for glucose metabolism: a naturally occurring variant that weakens MOTS-c is associated with higher T2D prevalence in men, especially physically inactive men, and the variant peptide lost the metabolic effects of native MOTS-c in male mice. The human data are associations (disease prevalence by genotype) and the treatment data come from mice, so this paper does not show that giving MOTS-c to people prevents or treats diabetes.

Citation

Zempo H, et al. Aging (Albany NY). 2021;13(2):1692-1717. doi:10.18632/aging.202529. PMID: 33468709

See Also

• Parent compound: MOTS-c