MENTSH: A novel mitochondrial microprotein linked to a SNP associated with type 2 diabetes.

RATIONALE: Obesity and type 2 diabetes (T2D) are growing threats to human health, and their genetic basis is complex and not fully understood. Furthermore, the mitochondrial genome has been shown to encode for many microproteins that have a variety of biological effects. In this study we explore a newly discovered mitochondrial-derived microprotein (MDP) that may be responsible for some forms of diabetes in humans. METHODS: We have performed a mitochondrial genome wide interaction study (MiWIS) and discovered a SNP that lies within the gene for an MDP and is associated with type 2 diabetes. We then used cell culture to confirm that this MDP has biological activity and used mass spectrometry to detect it. This novel MDP and more potent analogues were then administered in murine, in vivo studies in models of diabetes and obesity to determine the effects. Further analysis of the in vivo studies was performed with transcriptomic and proteomic techniques. RESULTS: Our MiWIS found a SNP associated with type 2 diabetes in 3 independent cohorts that is found within a novel MDP that we have called MENTSH (MDP Encoded in the ND-Two Subunit of Humans). This common SNP is found in populations indigenous to the Americas that interrupts the start codon of MENTSH. Murine in vivo studies demonstrate that MENTSH administration improves insulin signaling, while analogues of MENTSH can potently block weight gain caused by a high fat diet. Mechanistically, our studies show that MENTSH activates AKT signaling in muscle, while reducing AKT signaling in fat. CONCLUSIONS: These observations highlight a new cause of metabolic dysfunction in a vulnerable population, suggesting that MENTSH could be an innovative, precision medicine approach to treating T2D.