Abstract

A polymorphism MOTS-c, a mitochondrial-derived miniprotein, was reported to be associated with longevity in humans. Previous reports showed that MOTS-c regulates senescence in cells, enhances physical capacity in old mice and in humans. However, it is still unknown how MOTS-c is able to intervene the cellular senescence, what tissue or cell-type MOTS-c targets, and whether the regulation of aging by MOTS-c can lead to the prevention of aging- or senescence-induced disorders. Here, using S961 (or senescence)-induced mouse model, we show that MOTS-c is capable of targeting pancreas and is able to prevent senescence-induced diabetes. To test how MOTS-c is associated with β cell senescence, we firstly assess whether β cell senescence is associated with MOTS-c expression using pancreatic β cells isolated from 12-week-old mice. After isolation, pancreatic β cells were treated with H2O2 in concentration-dependent manner. Treatment of H2O2 lowered MOTS-c expression in concentration-dependent manner, but increased other senescence-related markers such as β-gal expression. Furthermore, MOTS-c treatment decreased H2O2-induced senescence-associated β-gal expression and SASPs (i.e., IL-1). To understand the inhibitory effect of MOTS-c against β cell senescence in vivo, we have transplanted S961-osmotic pump in 28-week-old mice with or without MOTS-c for 2 weeks. Mice treated with MOTS-c showed lowered random glucose level (310 mg/dL versus 180 mg/dL) and decreased level of pancreatic β-gal expression compared to S961-treated mice. Also, an i.p. glucose tolerance test (IPGTT) in 30-week-old mice revealed that MOTS-c treatment significantly improved glucose clearance. As a result, we showed that senescence/S961-induced diabetes were inhibited by MOTS-c treatment. B.Kong: None. S.Hong: None. Y.Cho: Consultant; LG Chem. Ministry of Health & Welfare, Republic of Korea (HI14C1277)