The mitochondrial-encoded MOTS-c prevents pancreatic islet destruction in autoimmune diabetes

Mitochondria are principal metabolic organelles that are increasingly unveiled as immune regulators. However, it is currently not known whether mitochondrial-encoded peptides modulate T cells to induce changes in phenotype and function. Here, we found that MOTS-c prevented autoimmune β-cell destruction via phenotypical and functional changes of T cells in NOD mice, a type 1 diabetes (T1D) animal model. MOTS-c ameliorated the development of hyperglycemia and reduced islet-infiltrating immune cells. Furthermore, adoptive transfer of T cells from MOTS-c-treated NOD mice significantly decreased the incidence of diabetes in NOD-SCID mice. Metabolic and genomic analysis revealed that MOTS-c modulated T cell phenotype and function by regulating TCR/mTORC1 pathway. We observed that T1D patients had a lower serum MOTS-c level than healthy controls. Furthermore, MOTS-c reduced T cell activation by alleviating T cells from the glycolytic stress in T1D patients suggesting a potential therapeutic implication. Our findings indicate that the MOTS-c acts as a regulator of T cell phenotype and function in autoimmune diabetes. NOD mice were treated with either vehicle (non-specific scrambled MOTS-c peptide) or MOTS-c (0.5 mg/kg/day; IP) daily in the morning up to 18 or 30 weeks of age. Random blood glucose (RBG) level and body weights were measured in the morning twice every week for all types of mice (Accu-Chek).