A previously unknown microprotein hidden within the human mitochondrial genome may help explain certain forms of Type 2 diabetes and could point toward a new, precision-medicine approach to treating it, according to a new USC study.
Obesity and Type 2 diabetes are among the fastest-growing threats to human health, yet their genetic underpinnings remain only partly understood. While most disease-gene research focuses on the larger set of DNA found in the nucleus within cells, the much smaller genome found in mitochondria - cells' energy factories - is now known to encode a family of microproteins with wide-ranging biological effects.
The new study adds a striking example to that list, said Pinchas Cohen, the study's senior author, USC Distinguished Professor and dean of the USC Leonard Davis School of Gerontology. The findings were published July 20 in the journal Theranostics.
A genetic clue in a vulnerable population
In a mitochondrial genomewide interaction study using health and genetic data from more than 15,000 adults, the team identified a single-nucleotide polymorphism (SNP, or "snip") associated with Type 2 diabetes. A SNP is a common type of genetic variation representing a difference in a single nucleotide, or individual "building block" of DNA. SNPs can play a role in individuals' different responses to certain medications, environmental factors or pathogens.
This genetic variant sits within the gene for a newly identified mitochondrial-derived microprotein, which the researchers have named MENTSH (MDP Encoded in the ND-Two Subunit of Humans).
Notably, this common variant is found most frequently in populations indigenous to the Americas and in 20% of Mexican and Mexican American individuals. The SNP disables MENTSH's "start codon," the portion of the gene that would normally signal the cell to start producing the microprotein. The discovery suggests this SNP may be a genetic contributor to metabolic disease in a population that bears a disproportionate burden of diabetes.
From discovery to therapeutic candidate
The researchers confirmed that MENTSH is a genuine, biologically active microprotein using cell-culture experiments and detected it directly using mass spectrometry. They then tested MENTSH and more potent engineered analogues in mouse models of diabetes and obesity.
In these preclinical studies, administering MENTSH improved insulin signaling, while MENTSH analogues potently blocked weight gain in mice fed a high-fat diet. Analyses pointed to a tissue-specific mechanism: MENTSH activates signaling for an enzyme called AKT in muscle but simultaneously reduces AKT signaling in fat, a pattern consistent with improved metabolic health.
"What's exciting is that this molecule appears to act differently in muscle versus fat, which is exactly the kind of targeted effect you'd want in a metabolic therapy," said USC Leonard Davis School Research Associate Professor of Gerontology Kelvin Yen, the study's first author.
Toward precision medicine
Together, the results identify a new biological cause of metabolic dysfunction and suggest that MENTSH-based therapies could one day offer a precision-medicine approach to Type 2 diabetes, particularly for individuals who carry this SNP. The presence of this genetic variant can be easily screened for and could serve as a test for diabetes risk.
The authors emphasize that these findings are preclinical. Further research, including additional safety and efficacy studies, will be required before MENTSH or its analogues can be evaluated in humans.
"For the first time, we've connected a mitochondrial microprotein to diabetes risk in a specific population, which opens the door to treatments tailored to the people who need them most," said co-author Jerome Rotter, a professor at the Lundquist Institute for Biomedical Innovation.
MENTSH could represent an exciting new therapeutic target for diabetes and obesity: a muscle-sparing weight loss peptide, Cohen said.
"This discovery not only represents a potential novel therapeutic for diabetes and obesity, which are major problems around the world, but it also unravels a new cause of diabetes in Hispanics, who are known to be disproportionately affected by these conditions," he said.
About the study: Additional authors included Ricardo Ramirez, Hiroshi Kumagai, Ana Silverstein, Roberto Vicinanza, Melanie Flores, Zeferino Reyna, Su-Jeong Kim, Noel Guerrero, Hemal H. Mehta, Junxiang Wan, Zhongzheng Niu, Carrie V. Breton, Thalida Em Arpawong and Eileen Crimmins of USC; Brendan Miller of the Salk Institute for Biological Studies; Jie Yao, Xiuqing Guo and Kent D. Taylor of the Lundquist Institute; Morgan Levine of Altos Labs; Jihui Sha and James Wohlschlegel of UCLA; and Maria C. Kenney of the University of California, Irvine.
The study was supported by grants from the National Institutes of Health (P30AG068345, R35 GM153408, R01AG068405, R01AG069698 and P30AG094848); the Navigage Foundation; the Ella Fitzgerald Charitable Foundation; the Hanson-Thorell Family Research Award; the Hinrich Foundation; the Hevolution Foundation (HF-AGE-23-1273964-51); and the Hinrich Endowment for Mitochondrial Genetics at the USC Leonard Davis School.
