The discovery of mitochondrial microtein opens the route for the treatments of obesity and aging

Like the bees that breathe life in gardens, providing pollen and flowers blooming, small cellular machines called mitochondria breathe life in our body, dipping with energy as they produce the fuel that dominates each of our cells. Maintaining mitochondrial metabolism requires influx of many molecules and proteins-some of which have not yet been discovered.

Researchers at the Salk Institute are more careful whether mitochondria are based on microproarothein small proteins that were difficult to find and were therefore underestimated for their role in health and diseases. In their new study, a microtein discovered just last year in the Salk, called SLC35A4-MP, was found to play a critical role in keeping mitochondrial structure and the regulation of metabolic stress in the fat cells. Findings plant seeds for future treatments based on microproaroteins for obesity, aging and other mitochondrial disorders.

The study, published in Scientific progress On August 29, 2025, it is part of a series of recent discoveries in the Salk that present the functional importance of microproteins in cell biology, metabolism and stress.

Microproteins have long been rejected as accidental genetic garbage, but our work adds to a growing body of research that proves that many of them are truly critical regulators of cell physiology. Here we reveal that a microprotein is responsible for maintaining mitochondrial structure and function in fat brown tissue, which regulates body temperature and energy balance. “

Alan Saghatelian, senior writer, professor and chair Dr. Frederik Paulsen in Salk

At the end of spring 2024, the Saghatelian lab discovered the genetic code for the SLC35A4-MP hidden in an upright open reading frame in a clone of Messenger RNA (MRNA). The long-term belief was that each MRNA clone encodes for a single protein-one to a protein mRNA ratio, always. Thus, when scientists found additional sections of genetic material- upstairs open reading frames in mRNA clones, they thought it should be either 1) randomly non-coded garbage or 2) regulatory code that affects the translation of this mRNA.

However, as genetic detection and sequence technology became more sophisticated, the researchers soon realized some of these upstream open reading frameworks codified for functional microteins. This discovery has brought a completely new dimension to cell life, as microteins are very hidden in missing openly open reading frameworks are now in full bloom-ready to remove and study.

Some of the first functional microprotins described participated in metabolism and mitochondrial regulation. This includes the study of Saghatelian 2024, in which the workshop first discovered the SLC35A4-MP on the walls of mitochondria. Further tests suggest that microprootin can help maintain healthy cellular metabolism.

But these findings were based on data collected from biochemical tests in test tubes and cells grown on Petri dishes. To fully confirm and describe the normal role of the SLC35A4-MP, they should test its operation on a live system.

“The SLC35A4-MP is one of the first microteins to be functional in mice,” says first writer Andréa Rocha, a postdoctoral researcher at the Saghatelian laboratory. “Indeed, we have found that the SLC35A4-MP regulates mitochondrial function and lipid metabolism in mice, which really shows that microteins cannot be ignored as we look for biological agents that regulate health.”

To classify the SLC35A4-MP, the researchers examined an exemplary metabolic tissue that works its mitochondria particularly hard: brown fat. Brown adipose cells are metabolic demanding as they regulate energy balance and body temperature. The researchers removed the SLC35A4-MP entirely of brown mouse brown cells and then caused metabolic stresses such as cold exposure or a high fat diet.

Without SLC35A4-MP, mice could not call their metabolism during the cold exposure. Their mitochondria were structurally compromised, enlarged, dysfunctional and inflammatory. In addition to mitochondria, other parts of brown fat cells were also affected. The researchers saw signs of internal redevelopment of cells and further inflammation-presenting metabolic decline in obesity-related conditions.

The findings demonstrate the fundamental role played by the SLC35A4-MP in regulating the function of brown fat cells and the response to metabolic stress. And because the mitochondria, our cellular bees, are found in every type of cell in the body, the findings extend everywhere. The SLC35A4-MP could be a strong therapeutic target for any disease or disorder that affects metabolic and mitochondrial function, from obesity to and beyond aging.

The research of microteins is ultimately achieved in life and the group sees bright flowers in front of the search for more functional microteins.

“As scientists have managed to add more microteins to our protein databases, the question remained, do these microprotins have any normal importance?” says Saghatelian. “And the study says yes, they are important normal regulators. I hope it adds more fuels to the study of microproarians moving forward.”

Other writers include Antonio Pinto, Jolene Diedrich, Huanqi Shan, Eduardo Vieira de Souza, Joan Vaughan and Salk Mark Foster. Christian Schmedt of the Novartis Research Foundation and incorporates bio -science. Guy Perksin and Mark Ellisman of UC San Diego. Kaja Plucińska and Paul Cohen of Rockefeller University. and Srinath Sampath of Foundation Research Novartis and UC San Diego.

The project was supported by the National Institutes of Health (P30 CA014195, R01 GM102491, U24 NS120055, R01 NS108934, R01 GM138780, R01 AG06549, S10 OD021784, RC2 DK129961, NIA R08, NIA R01 R01 R01 AG062479, NIMH RF1 MH129261, NIH-NCI CCSG P30 CA014195, Nih-Nia San Diego Nathan Shock Center P30 AG068635 Henry L. Guenher Foundation, Helmsley Charitable Trust and George E. Hewitt Foundation for medical research.