The discovery of the mitochondrial microprotein opens the path to obesity and aging therapy

Like bees breathing life in the gardens, providing pollen and blooming flowers, small cellular machinery called mitochondria breathes life into our bodies, buzzing with energy, because they produce fuel that drives every of our cells. Maintenance of mitochondrial metabolism requires the contribution of many molecules and proteins-which have not yet been discovered.

Scientists of the Salk Institute are looking closely at mitochondria, microprotein proteins, which were difficult to find, and thus underestimated for their role in health and illness. In its new microprotein study, discovered last year in Salk, called SLC35A4-MP, plays a key role in maintaining the structure of mitochondria and regulation of metabolic stress in mouse fat cells. Discoveries are planted by the grain of future methods of treating obesity, aging and other mitochondrial disorders.

The study, published on August 29, 2025, is part of a series of recent discoveries in SALK, which show the functional importance of microfrotins in cell biology, metabolism and stress.

Microproteins have long been rejected as random genetic garbage, but our work increases the growing number of tests, which shows that many of them are actually key regulators of cellular physiology. Here, we reveal that the microfrotin is responsible for preserving the mitochondrial structure and function in brown fat tissue, which regulates body temperature and energy balance. “

Alan Saghatelian, senior author, professor and dr Frederik Paulsen in Salk

In the late spring of 2024, the Saghatelian laboratory was discovered by the genetic code for SLC35A4-MP hidden in an open reading frame Messenger RNA (MRNA). The long-term has found that each MRNA thread always codes for a single ratio of one-to-one protein, always. So, when scientists found additional sections of the genetic material- an open reading frame for MRNA bands, they thought they had to be either 1) random junk garbage or 2) the regulatory code that affects the translation of this MRNA.

But because the genetic probation and sequencing technology has become more sophisticated, scientists soon realized some of the open read frames encoded for functional microproteins. This discovery has brought a completely new dimension of cellular life, because the microproteins have long been hidden in the disregard of open reading frames are now fully bloody to throw them away and examine them.

Some of the first functional microproteins that have been described were involved in metabolism and mitochondrial regulation. This includes the Saghatelian 2024 study, in which the laboratory was first discovered by SLC35A4-MP in the walls of Mitochondria. Further tests suggested that microprotein could help maintain healthy cellular metabolism.

But these discoveries were based on data collected from biochemical tests in test lamps and cells bred in Petri vessels. To fully confirm and describe the physiological role of SLC35A4-MP, they would have to test its function in a living system.

“SLC35A4-MP is one of the first microproteins that are functionally characterized in mice,” says the first author of Andréa Roch, a doctoral researcher at the Saghatelian laboratory. “We actually found that SLC35A4-MP regulates the function of mitochondria and lipid metabolism at mice, which really shows that microprotein cannot be overlooked when we are looking for biological factors regulating health.”

To classify SLC35A4-MP, scientists looked at exemplary metabolic tissue that works particularly hard on mitochondria: brown fat. Brown fat cells are metabolically demanding because they regulate energy balance and body temperature. Scientists removed the SLC35A4-MP completely from mouse brown fat cells, and then induced metabolically stressful events, such as cold exposure or high-fat diet.

Without SLC35A4-MP, mice were unable to choose metabolism when exposure to cold. Their mitochondria was structurally threatened, enlarged, dysfunctional and inflammatory. In addition to mitochondria, other parts of brown fat cells were also affected. Scientists saw signs of the reconstruction of the interior of the cells and further inflammation-metabolic decrease in the conditions related to obesity.

The discoveries show the basic role of SLC35A4-MP in the regulation of brown fat cell functions and reaction to metabolic stress. And because mitochondria, our buzzing cell bees, are in every type of cells in the body, the results also extend everywhere. SLC35A4-MP can be a powerful therapeutic goal for any disease or disorders that affect the metabolic and mitochondrial function, from obesity to aging and more.

Mikroprotein studies are finally developing, and the band sees how bright it blooms in search of more functional microproteins.

“Because scientists were able to add more microproteins to our protein databases, the question has remained, do these microproteins have any physiological significance?” says saghatelian. “And our study says so, they are important physiological regulators. I hope that it adds more fuel to testing microfrides forward.”

Pino Dierich, Shan. Christian Research Foundation; Guy Perkin and Mark Ellisman from UC San Diego; Pucińska and Paul Cohens from Rockefer University; Said UC from Diego.

The works were supported by the National Institutes of Health (P30 CA014195, R01 GM102491, U24 NS120055, R01 NS108934, R01 GM138780, R01 AG065549, S10 from021784, RC2 DK129961, Nia R01 AG081037, nia, nia, nia, nia, nia, nia, nia, nia Nia R01 AG062479, NIEH RF1 MH129261, NIH-NCI CCSG P30 CA014195, NIH-NIH SAN DIEGO NATHAN SHOCK Center P30 AG068635, NIH-NIA Tests of Alzheimer’s disease Centrum P30 AG062429), National Science Foundation (2014862), American Heart Association Allen Initiative, California Institute for Regenerative Medicine, Henry L. Guenther Foundation, Helmsley Charitable Trust and George E. Hewitt Foundation for Medical Research.