Mitoregulin (Mtln), a 56-amino-acid-long mitochondrial peptide, is conserved in vertebrates. It is known to enhance the function of respiratory complex I, likely by modulating lipid composition, and is involved in oxidative metabolism, fatty acid metabolism, and maintaining mitochondrial membrane integrity. Gene knockout mouse models have been crucial for studying its functions [1,2,3,4,5].

In Mtln knockout mice, several phenotypes have been observed. They develop 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 knockout mice, there are decreased respiratory complex I activity, excessive cardiolipin damage, and in aged male knockout mice, an increased frequency of renal proximal tubules' degeneration, while aged female knockout mice show a decreased glomerular filtration rate [2]. Additionally, Mtln knockout mice have reduced muscle strength, with mitochondrial creatine kinase octamer dissociation and suboptimal respiratory chain performance [4].

In conclusion, Mtln is essential for oxidative metabolism, fatty acid metabolism, and maintaining mitochondrial function. The use of Mtln knockout mouse models has revealed its role in obesity development, as well as its impact on muscle and kidney function, providing insights into potential disease mechanisms related to mitochondrial dysfunction.