Mitoregulin (Mtln), a 56-amino-acid-long mitochondrial peptide, is conserved in vertebrates. It localizes in mitochondria and is crucial for oxidative phosphorylation, fatty acid metabolism, and maintaining mitochondrial membrane integrity [1,2,3]. Mtln enhances the function of respiratory complex I, likely through modulating lipid composition, and is involved in pathways such as the tricarboxylic acids cycle [1].

In Mtln knockout mouse models, several phenotypes were observed. These mice developed obesity on a high-fat diet, with enhanced fat accumulation, elevated serum triglycerides, and exhaustion of tricarboxylic acids cycle intermediates, suggesting suboptimal oxidation of respiration substrates by mitochondria lacking Mtln [1]. In muscle and kidney tissues of these KO mice, decreased respiratory complex I activity, excessive cardiolipin damage, and abnormal creatine kinase oligomerization were found [2]. Mtln-KO mice also suffered worse myocardial ischemia-reperfusion injury, indicating its role in cardioprotection [3].

In conclusion, Mtln plays essential roles in mitochondrial-related functions like oxidative metabolism, lipid metabolism, and membrane integrity. The Mtln KO mouse models have revealed its significance in conditions such as obesity, kidney-related disorders, and cardiac ischemia-reperfusion injury, providing insights into potential therapeutic targets for these diseases.