Unveiling the Role of Microproteins‌ in Cellular Energy

Like bees breathing life into gardens, providing​ pollen and making ‌flowers blossom, little ‌cellular⁤ machines called ‌mitochondria breathe life into our⁣ bodies, buzzing ​with energy ‍as‌ they ⁢produce the fuel ⁣that powers each of our cells. maintaining mitochondrial metabolism requires input from many ‌molecules⁣ and proteins -⁣ some of which have yet to be ⁢discovered.

Salk Institute researchers are taking a closer ⁣look ⁣at whether mitochondria rely on microproteins – small proteins that have been difficult to ⁢find and, consequently, underestimated for their role‌ in ⁣health and ​disease. in their new study, a microprotein discovered just last year at Salk, called SLC35A4-MP, was found to⁣ play‌ a critical ​role in upholding ⁢mitochondrial structure and ⁢regulating metabolic stress in mouse ‌fat cells. The findings plant the seed for future microprotein-based treatments for obesity, aging, and‍ other‌ mitochondrial ⁢disorders.

The⁤ study, published in Science⁣ Advances on August 29, 2025, ‌is part​ of a series of​ recent discoveries at⁢ salk that showcase the functional importance of microproteins in cellular biology, metabolism, ⁤and stress.

“Microproteins have long been dismissed as random genetic junk,​ but our work adds to⁢ a growing body of research demonstrating that many of them are actually crucial regulators of ⁤cell physiology,” says senior author Alan saghatelian,‌ professor and Dr. Frederik Paulsen Chair at Salk. ⁣”Here we reveal that a microprotein is responsible for preserving mitochondrial structure and function in brown fat tissue,⁣ which regulates body temperature and energy balance.”

The Changing Landscape of Genetic Understanding

In the late spring of⁤ 2024,Saghatelian’s‍ lab ​discovered the genetic code for SLC35A4-MP hidden in an upstream open reading frame ⁢on⁤ a strand‌ of messenger RNA (mRNA). The longstanding belief ​was that each mRNA strand codes ⁢for a single ‌protein – a ‌one-to-one ratio‌ of mRNA-to-protein, always. ⁤So, when scientists found additional ​sections⁣ of⁢ genetic material – upstream open reading⁢ frames – on mRNA⁣ strands, they thought they must ‍be either 1) random noncoding junk or​ 2) regulatory‌ code⁣ that ⁤influences the translation of ⁣that ​mRNA.

But as genetic probing and​ sequencing technology became ⁢more⁣ elegant, researchers‍ soon realized some of those⁢ upstream open reading frames ‌coded for functional microproteins. This discovery brought an entirely new dimension to cellular life, as microproteins ⁤long hidden in disregarded upstream open reading frames are now in full bloom – ready to be plucked ‍and studied.

Some of the first functional microproteins to be described were​ involved in‌ metabolism and mitochondrial regulation. This includes Saghatelian’s 2024 study, in which the lab first discovered‍ SLC35A4-MP⁤ in the walls‍ of⁤ mitochondria. Further tests suggested the microprotein might be ⁤helping maintain healthy cellular metabolism.

But these findings were based on data collected ‌from biochemical assays in test tubes and‍ cells cultured in petri dishes. To fully confirm and describe ‍SLC35A4-MP’s⁤ physiological​ role, they would have to test its function‌ in⁢ a living system.

“SLC35A4-MP is among the first microproteins to be‍ functionally characterized in mice,” says first​ author Andréa⁣ Rocha, a postdoctoral researcher in Saghatelian’s lab. “Indeed, we⁢ found ⁢that SLC35A4-MP ⁣regulates ‌mitochondrial⁣ function and lipid meta