Small Protein, Big Impact: Microprotein Discovery Offers Hope for Obesity and Aging

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Researchers have uncovered a tiny but powerful protein that helps keep our cells’ energy factories humming – a discovery that could spark new approaches to tackling obesity and age-related decline. Scientists at the Salk Institute in La Jolla found that a  “microprotein”  in mouse fat cells plays a critical role in maintaining healthy  mitochondria , the structures that generate energy in our cells. By preserving mitochondrial function, this diminutive protein helps cells burn fuel efficiently, which in turn could influence body weight and the aging process. The findings shine light on how molecular biology connects to everyday health, opening the door to  science-backed strategies for better metabolism and longevity. Mature brown fat cells from a mouse, with the newly discovered microprotein shown in red inside mitochondria (green) and nuclei in blue. This tiny protein helps preserve mitochondrial health under stress. (Credit: Salk Institute) Mighty Mitochondria in ...

Microprotein SLC35A4‑MP: a tiny regulator of mitochondrial health

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Tiny proteins hidden in our genetic code are changing the way scientists think about cell biology. A research team from the Salk Institute recently reported that a newly discovered microprotein, SLC35A4‑MP, helps maintain the structure and function of mitochondria – the energy‑producing “powerhouses” of our cells. Microproteins like SLC35A4‑MP are encoded in sections of messenger RNA that were once dismissed as non‑coding junk. As analytical techniques improved, researchers realized these regions can encode functional proteins that influence metabolism and stress responses.

Why it matters

Mitochondria convert nutrients into energy, regulate body temperature and help maintain metabolic balance. When mitochondrial function declines, metabolic diseases such as obesity and age‑related disorders can follow. In the Salk study, researchers focused on brown fat—a metabolically demanding tissue that generates heat. They removed the gene encoding SLC35A4‑MP from brown fat cells in mice and subjected the animals to cold exposure or a high‑fat diet. Without the microprotein, the animals could not increase their metabolism when cold, and their mitochondria were enlarged, structurally disorganized and inflamed. These defects extended beyond the organelle: the cells showed signs of remodeling and inflammation similar to what is seen in obesity‑related conditions.

The findings show that SLC35A4‑MP plays a fundamental role in regulating mitochondrial stress responses. Because mitochondria are found in every cell type, this microprotein may become a therapeutic target for diseases involving metabolic and mitochondrial dysfunction, ranging from obesity to aging.

Key points from the study

  • Discovery of SLC35A4‑MP: Senior author Alan Saghatelian, a professor and Dr. Frederik Paulsen Chair at the Salk Institute, and his colleagues discovered the genetic code for SLC35A4‑MP in 2024 within an upstream open reading frame on a messenger RNA strand. Upstream reading frames were once thought to be non‑coding, but new sequencing and ribosome‑profiling methods showed that they can encode functional microproteins.

  • Physiological role in mice: To test whether SLC35A4‑MP has a biological role, the team generated mice lacking the microprotein in brown fat. These mice could not properly regulate their metabolism during cold exposure, and their mitochondria showed structural damage, inflammation and an inability to adjust to metabolic stress.

  • Implications for health: By preserving mitochondrial structure and helping brown fat respond to metabolic stress, SLC35A4‑MP may support metabolic health. The researchers suggest that microprotein‑based therapies could eventually help treat obesity, aging and other mitochondrial disorders.

Researchers involved

  • Alan Saghatelian, PhD – Professor and Dr. Frederik Paulsen Chair at the Salk Institute; senior author and microprotein specialist.

  • Andréa Rocha, PhD – Postdoctoral researcher in Saghatelian’s lab and first author; she conducted the functional experiments in mice.

  • Additional team members: Antonio Pinto, Jolene Diedrich, Huanqi Shan, Eduardo Vieira de Souza, Joan Vaughan and Mark Foster (Salk Institute); Christian Schmedt (Novartis Research Foundation and Integrate Bioscience); Guy Perksin and Mark Ellisman (UC San Diego); Kaja Plucińska and Paul Cohen (Rockefeller University); and Srinath Sampath (Novartis Research Foundation and UC San Diego).

Related books and resources:

To delve deeper into mitochondrial biology and health, here are some relevant books. These direct links include your Amazon Associates ID: