Researchers at the University of Southern California have discovered a biologically active microprotein encoded within the mitochondrial genome whose absence, caused by a population-specific genetic variant, may contribute to elevated metabolic disease risk.
Scientists have identified a previously unknown microprotein hidden within the human mitochondrial genome that could help explain why some people are more susceptible to Type 2 diabetes and may eventually lead to a new precision medicine approach to treatment.
The discovery, made by researchers at the University of Southern California (USC), looks at the genetic factors behind diabetes and obesity, two of the world’s fastest-growing health challenges.
New genetic link discovered
While most research into the genetics of disease has focused on DNA found in the cell nucleus, the much smaller mitochondrial genome appeared to be an important source of biologically active microproteins.
In a genomewide interaction study involving health and genetic data from more than 15,000 adults, researchers identified a single-nucleotide polymorphism (SNP) linked to Type 2 diabetes. SNPs are common genetic variations involving a change in a single DNA building block and can influence an individual’s response to medicines, environmental factors and disease.
In a genomewide interaction study involving health and genetic data from more than 15,000 adults, researchers identified a single-nucleotide polymorphism (SNP) linked to Type 2 diabetes
The genetic variant was found within the gene for a newly discovered mitochondrial-derived microprotein, named MENTSH (MDP Encoded in the ND-Two Subunit of Humans).
Researchers found the variant is most common among populations indigenous to the Americas and is present in around 20 percent of Mexican and Mexican American individuals. The SNP prevents the production of MENTSH by disabling the gene’s start codon, suggesting it could contribute to the increased burden of metabolic disease seen within these populations.
Encouraging laboratory results
The research team confirmed that MENTSH is a genuine, biologically active microprotein through laboratory experiments and direct detection using mass spectrometry.
Scientists then tested both MENTSH and more potent engineered versions of the molecule in mouse models of obesity and diabetes. In these preclinical studies, MENTSH improved insulin signalling, while the engineered analogues significantly reduced weight gain in mice fed a high-fat diet.
The research team confirmed that MENTSH is a genuine, biologically active microprotein through laboratory experiments and direct detection using mass spectrometry
The researchers also discovered that MENTSH acts differently depending on the tissue. It activates AKT enzyme signalling in muscle while reducing AKT signalling in fat tissue which is usually associated 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 Research Associate Professor of Gerontology Kelvin Yen, the study’s first author.
Potential for precision medicine
The findings suggest MENTSH-based therapies could one day offer a personalised approach to treating Type 2 diabetes, particularly for people who carry the newly identified genetic variant. Researchers say the SNP can be identified through genetic screening and could potentially be used to assess diabetes risk.
The findings suggest MENTSH-based therapies could one day offer a personalised approach to treating Type 2 diabetes
However, the work is still at the preclinical stage and further research will be needed to establish the safety and effectiveness of MENTSH-based treatments before they can be tested 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.
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