Discovery of microprotein may explain diabetes risk in Hispanic populations

Researchers at the University of Southern California have identified a previously unknown microprotein within human mitochondrial DNA that may help to explain a genetic form of type 2 diabetes that disproportionately affects Mexican heritage communities

Researchers at the University of Southern California (USC) have identified a previously unknown microprotein hidden within the human mitochondrial genome that may help to explain certain forms of type 2 diabetes (T2DM). The discovery could point towards a novel, precision-medicine approach to treat the condition.

Obesity and T2DM have become among the fastest-growing threats to human health, yet their genetic underpinnings remain only partly understood. While most disease-gene research has focused on the larger set of DNA found in the cell’s nucleus, the far smaller genome housed within mitochondria – often described as the cell’s energy factories – is now known to encode a family of microproteins with wide-ranging biological effects.

Dr. Pinchas Cohen, the study’s senior author, a USC distinguished professor and dean of the USC ‘Leonard Davis School of Gerontology’, said the study added a striking example to that list.

In a mitochondrial genome-wide interaction study using health and genetic data from more than 15,000 adults, the team identified a single-nucleotide polymorphism (SNP) –sometimes called a ‘snip’ – associated with T2DM. A SNP is a common type of genetic variation representing a difference in a single nucleotide of DNA. SNPs can play a role in how individuals respond differently to certain medications, environmental factors or pathogens.

This genetic variant sits within the gene for a previously unidentified mitochondrial-derived microprotein, which the researchers have named MENTSH – which is an abbreviation for ‘MDP encoded in the ND-Two subunit of humans’.

MDP denotes a mitochondrial-derived peptide, the established term for this class of molecule, while ND-Two refers to ND2, a gene within the mitochondrial genome that forms part of Complex I of the cell’s respiratory chain.

Notably, this common variant occurs most frequently in populations indigenous to the Americas and has been found in 20 per cent of Mexican and Mexican American individuals. The SNP disables the start codon of the MENTSH gene, the section of DNA that would normally signal the cell to produce the microprotein. The discovery suggests that this SNP may be a genetic contributor to metabolic disease in a population that bears a disproportionate burden of diabetes.

The researchers confirmed that MENTSH is a genuine, biologically active microprotein through cell-culture experiments and detected it directly by means of mass spectrometry. They then tested MENTSH, together with more potent engineered analogues, in mouse models of diabetes and obesity.

In these preclinical studies, the administration of MENTSH improved insulin signalling, while MENTSH analogues potently blocked weight gain in mice fed a high-fat diet. Analyses pointed to a tissue-specific mechanism whereby MENTSH appeared to activate signalling for an enzyme called AKT in muscle, while simultaneously reducing AKT signalling in fat tissue, a pattern consistent with improved metabolic health. AKT is more commonly known as protein kinase B.

“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 Dr. Kelvin Yen, USC Leonard Davis Research Associate Professor of Gerontology and the study’s first author.

Together, these results identify a novel biological cause of metabolic dysfunction and suggest that MENTSH-based therapies could, in time, offer a precision-medicine approach to the treatment of T2DM, particularly for those who carry this SNP. The presence of the genetic variant can be readily screened for and could serve as a test for diabetes risk.

“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 Dr. Jerome Rotter, a professor at the Lundquist Institute for Biomedical Innovation, part of the Harbor-UCLA Medical Center, Torrance, Los Angeles.

Cohen said MENTSH could represent a promising therapeutic target for diabetes and obesity with the possibility of building a muscle-sparing weight-loss peptide.

“This discovery not only represents a potential new therapeutic [direction] 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,” Cohen added.

For further reading please visit: 10.7150/thno.134637