MENTSH—A Mitochondrial Microprotein and SNP-Associated with Diabetes in People with Native American Ancestry

Introduction & Objective: The mitochondria has been implicated in the etiology of diabetes, but the role of mitochondrial microproteins in this process has not been thoroughly investigated. Furthermore, diabetes prevalence differs between races and ethnicities, and although social economic factors are a major cause, we wanted to examine if genetics also played a role. Our objective was to 1) determine if variations in the mitochondrial genome correlated with diabetes and 2) determine if mitochondrial microproteins played a role in diabetes.

Methods: We performed a mitochondrial genome focused GWAS on the Health and Retirement Study, which a study of over 15,000 individuals over the age of 50 years in the USA. In vivo studies were performed in mice on a high fat diet (60% fat) or ob/ob mice that lack leptin. Western blots and other molecular biology techniques were performed using standard procedures.

Results: While performing a mitochondrial focused GWAS (miWAS), we have discovered a common SNP in populations of Native American descent that is associated with an increased chance of diabetes and also interrupts the start codon of a novel mitochondrial microprotein that we call MENTSH. Supporting this finding, administration of this microprotein in different mouse models of diabetes (60% high fat diet and ob/ob mice that lack leptin) can attenuate the disease progression. Treatment with MENTSH and MENTSH analogues improved glucose tolerance as measured by GTT and reduced weight gain. Molecularly, we find that MENTSH differentially affects AKT phosphorylation in muscle and fat.

Conclusion: We have discovered a SNP and a previously unknown microprotein that are now implicated in diabetes. Administration of this microprotein to mouse models of diabetes improves their outcomes. This discovery opens up the possibility of using MENTSH or its analogues as a novel therapeutic approach for diabetes.