Year: 2026
Type: article
Abstract: 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.
Source: Theranostics
DOI: 10.7150/thno.134637
Authors: Kelvin Yen, Ricardo Ramirez, Brendan Miller, Hiroshi Kumagai, Jie Yao, Morgan Levine, Xiuqing Guo, Jihui Sha, Ana Silverstein, Roberto Vicinanza, Kent D. Taylor, Melanie Flores, Zeferino Reyna, Su-Jeong Kim, Noel Guerrero, Hemal H. Mehta, Junxiang Wan, Zhongzheng Niu, Carrie V. Breton, Maria C. Kenney, Thalida Em Arpawong, James Wohlschlegel, Jerome I. Rotter, Eileen Crimmins, Pinchas Cohen
Institutions: University of Southern California, Salk Institute for Biological Studies, Tohoku University, The Lundquist Institute, Harbor–UCLA Medical Center, Altos Labs, University of California, Los Angeles, University at Buffalo, State University of New York, Washington University in St. Louis, University of California, Irvine
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $1,671
Awards: The Integration of Trans-omics for Precision Medicine (TOPMED) and Other Heart, Lung, Blood and Sleep (HLBS) Data Sets with the Data Commons, Metformin-Regulated Mitochondrial Peptides and their Effects on Aging, TOPMed Omics of Cardiovascular Disease in Diabetes, Multi-Ethnic Study of Atherosclerosis (MESA) Study, MESA, UCLA Clinical and Translational Science Institute, Wake Forest Clinical and Translational Science Award, Large Scale Sequencing and Analysis of Genomes, MESA, MESA Family Study, MESA, SUBCLINICAL CARDIOVASCULAR DISEASE STUDY--EBCT READING, MESA Family Study, MESA, TITLE: MULTI-ETHNIC STUDY OF ATHEROSCLEROSIS (MESA), Creating a National Resource for Genetic Research in Behavioral & Health Sciences, OPTION 3. 4/1/2014 - 3/31/2015. MULTI-ETHNIC STUDY OF ATHEROSCLEROSIS (MESA) - READING CENTER, NHLBI, MESA Family Study, MESA, MESA Family Study, SUBCLINICAL CARDIOVASCULAR DISEASE STUDY-ULTRASOUND, Whole-genome sequencing analysis of coronary atherosclerosis and related traits, The Integration of Trans-omics for Precision Medicine (TOPMED) and Other Heart, Lung, Blood and Sleep (HLBS) Data Sets with the Data Commons, NHLBI Data Stage Coordinating Center, CHARGE consortium: omics discovery for CVD and aging phenotypes, Expanding a National Resource for Genetic Research in Behavioral & Health Science, Institute for Clinical and Translational Research, MESA, The University of Southern California and Buck Institute Nathan Shock Center, MESA Family Study, MESA, The Integration of Trans-omics for Precision Medicine (TOPMED) and Other Heart, Lung, Blood and Sleep (HLBS) Data Sets with the Data Commons, The Integration of Trans-omics for Precision Medicine (TOPMED) and Other Heart, Lung, Blood and Sleep (HLBS) Data Sets with the Data Commons, Clinical and Translational Science Award, Ethnic-specific Effects of Mitochondrial DNA Variants and Environmental Factors on Cognitive Functioning and Dementia, Understanding Ubiquitin-dependent Regulation of Iron Metabolism using Mass Spectrometry, Diabetes Research Center (DRC), Los Angeles Claude D. Pepper Older Americans Independence Center, Health and Retirement Study: Yrs 35-40, UCLA Clinical and Translational Science Institute
OpenAlex ID: W7171486680