Christopher Auger, Hiroshi Nishida, Bo Yuan, Guilherme Martins Silva, Masanori Fujimoto, Mark Li, Daisuke Katoh, Dandan Wang, Melia Granath-Panelo, Jihoon Shin, Rose Witte, Jin-Seon Yook, Anthony R. P. Verkerke, Alexander S. Banks, Sheng Hui, Lijun Sun, Shingo Kajimura
Environmental adaptation often involves a shift in energy utilization toward mitochondrial fatty acid oxidation, which requires carnitine. Besides dietary sources of animal origin, carnitine biosynthesis from trimethyllysine (TML) is essential, particularly for those who consume plant-based diets; however, its molecular regulation and physiological role remain elusive. Here, we identify SLC25A45 as a mitochondrial TML carrier that controls carnitine biosynthesis and fuel switching. SLC25A45 deficiency decreased the carnitine pool and impaired mitochondrial fatty acid oxidation, shifting reliance to carbohydrate metabolism. Slc25a45 -deficient mice were cold-intolerant and resistant to lipid mobilization by glucagon-like peptide-1 receptor agonist (GLP-1RA), rendering them resistant to adipose tissue loss. Our study suggests that mitochondria serve as a regulatory checkpoint in fuel switching, with implications for metabolic adaptation and the efficacy of GLP-1RA–based anti-obesity therapy.