Longevity & Aging

Tiny Mitochondrial Microprotein Keeps Brown Fat Healthy and Metabolism Running

SLC35A4-MP is a mitochondrial microprotein encoded by an upstream open reading frame (uORF) within the SLC35A4 messenger RNA. Researchers at the Salk Institute generated knockout mice lacking SLC35A4-MP and found that brown adipose tissue (BAT) mitochondria became structurally disorganized, with disrupted cristae and abnormal lipid membranes. Cardiolipin levels — a lipid essential for mitochondrial membrane integrity and oxidative phosphorylation — fell significantly. The knockout mice showed impaired thermogenic capacity, reduced uncoupling protein 1 (UCP1) expression, and worsened metabolic outcomes on a high-fat diet. Expression of SLC35A4-MP was dynamically regulated during brown adipocyte differentiation and during cold exposure or obesity, suggesting the microprotein plays an active, context-dependent role in maintaining mitochondrial and metabolic health in brown fat.