After GLP-1, It's "Microproteins": Opening New Routes for Obesity and Aging Treatment - The Day the Common Belief of 'One mRNA = One Protein' Crumbles

1. What Was Discovered — "Tiny Yet Central"

"Microproteins" are extremely small proteins of around 100 amino acids that have long been considered "genetic noise." The Salk Institute has now clearly demonstrated in mice that one such protein, SLC35A4-MP, functions as a "keystone" in maintaining the mitochondrial structure of brown fat, influencing resistance under metabolic stress such as cold or high-fat diets. When SLC35A4-MP is deficient, mitochondria become enlarged, distorted, and inflamed, and energy metabolism fails to initiate. Since brown fat is central to maintaining body temperature and energy balance, its dysfunction affects the entire body's metabolism. Phys.org

2. Background — The End of the "One mRNA, One Protein" Era

Traditionally, the textbook understanding was that "one mRNA codes for one type of protein." However, small proteins independently translated from "upstream ORFs (uORFs)" located upstream of mRNA are being discovered one after another. SLC35A4-MP is one such protein, first reported in 2024 as a "single-pass transmembrane microprotein of 103 amino acids localized to the inner mitochondrial membrane (IMM)." The current paper examines its role at the organismal level in brown fat, substantiating its functional importance. PMC

3. Key Points of the Study — Knockout × Brown Fat × Metabolic Stress

The research team created mice deficient in SLC35A4-MP in brown fat. They investigated the metabolic response of brown fat under "stress tests" such as cold exposure and high-fat diets. The results showed that in deficient individuals, morphological collapse (enlargement, cristae abnormalities) and functional decline of brown fat mitochondria were observed, along with increased inflammation, leading to a failure to initiate the metabolism necessary for heat production. The maintenance of mitochondrial structure itself emerged as a bottleneck for metabolic adaptation. Phys.orgScience.org

Published in: Science Advances (August 29, 2025)
Paper Title (Abstract): SLC35A4-MP is a uORF-derived microprotein that regulates mitochondrial morphology and function in brown fat Science.org

Additionally, the raw data from proteomics has been made available, providing ample opportunity for reanalysis. A "reproducibility infrastructure" is being established to aid drug discovery research and verification in other tissues. EMBL-EBIproteomecentral.proteomexchange.org

4. Why It Matters — A Strategy Beyond GLP-1: "Mitochondrial Preservation"

The treatment of obesity, type 2 diabetes, and age-related diseases has undergone a seismic shift with the rise of GLP-1 receptor agonists. However, unlike GLP-1, which primarily targets appetite and eating behavior, the focus here is on the health of the cell's energy factory, the mitochondria. When mitochondrial structural preservation breaks down, brown fat cannot perform thermogenesis (non-shivering thermogenesis), slowing overall metabolism. Combined with previous studies on mitochondrial phospholipid composition and UCP1 regulation, **"engine maintenance"** of brown fat could become a promising axis for drug discovery. SLC35A4-MP is positioned as a candidate "mechanic" for this maintenance. Science.org

5. Context of the Entire Field — Toward "Microprotein Drug Discovery"

By 2025, results from CRISPR screenings identifying multiple microproteins functioning in adipocytes have been reported, clarifying the image of lipid metabolism and fat accumulation being controlled by tiny peptides. **The previously overlooked "dark proteome"** is coming to light, rapidly increasing the "seeds" of new targets for obesity and aging-related diseases. PNAS

6. Reactions on Social Media — The "Temperature Difference" Between Enthusiasm and Caution

• Lead Author Rocha (X): Emphasizes that this study builds on the 2024 IMM localization report and demonstrates function at the organismal level. Receives congratulatory replies from the research community. X (formerly Twitter)

• Clinician Account (X): Introduces the paper title while cautioning that it is a mouse study, pointing out the distance to human application. X (formerly Twitter)

• Media Official (Threads): Introduces the key points to the general public as a new microprotein involved in maintaining the mitochondrial structure of brown fat, mentioning the potential for drug discovery and attracting attention. threads.net

Overall, researchers and technical experts welcome it as a "milestone in mechanisms", while those closer to clinical practice are cautious, saying "human verification and pharmacology are yet to come." A healthy temperature difference is observed.

7. What Happens Next? — Three Practical Points

1. Target Validity (T): Does SLC35A4-MP function in tissues other than brown fat, such as skeletal muscle or liver? Mapping localization, expression, and phenotype is a priority. MDPI

2. Modality Selection (M): Enhance function with small molecules? Peptide administration? Or mRNA/gene therapy? IMM-localized proteins have high hurdles for druggability.

3. Human Extrapolation (H): Verification considering the plasticity and differences of human brown fat is necessary (human BAT exists even in adults and contributes to metabolism and temperature regulation). How to demonstrate both metabolic and safety aspects in preclinical studies. New England Journal of Medicine

8. Risks and Limitations — "Small Yet Complex"

• Species Differences: There is no guarantee that effects observed in mice will directly apply to humans.

• Complexity of Action Points: While SLC35A4-MP contributes to "structural preservation," specific molecular interactions and downstream networks remain unexplored.

• Druggability: The inner mitochondrial membrane is difficult to access with drug administration, requiring ingenuity in drug design.
  These indicate that this achievement is a "starting point." Science.org

9. Conclusion — "The Overlooked Small Key"

SLC35A4-MP was a small craftsman supporting the **"beams"** of the energy factory known as mitochondria. To tackle the "difficult terrains" of obesity, aging, and mitochondrial diseases, we are beginning to take up not only large hammers but also precise wrenches, i.e., microproteins. What is needed next are human data and modalities that reach the IMM. Phys.orgSalk Institute for Biological Studies

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