Mitoregulin (Mtln), a 56-amino-acid-long mitochondrial peptide conserved in vertebrates, is encoded by LINC00116 [1,6,7]. It plays a crucial role in oxidative metabolism, specifically enhancing the function of respiratory complex I, likely by modulating lipid composition. Mtln is also involved in fatty acid metabolism, contributing to processes like β-oxidation in adipocytes [1,2,4,6].

In Mtln knockout mouse models, several phenotypes have been observed. These mice develop obesity on a high-fat diet, with increased fat accumulation, elevated serum triglycerides, and exhaustion of tricarboxylic acids cycle intermediates, suggesting suboptimal oxidation of respiration substrates by mitochondria lacking Mtln [1]. In aged Mtln knockout mice, kidney-related phenotypes include decreased respiratory complex I activity, excessive cardiolipin damage, increased frequency of renal proximal tubules' degeneration in males, and decreased glomerular filtration rate in females [2]. Mtln knockout mice also show reduced muscle strength, mitochondrial creatine kinase octamer dissociation, and suboptimal respiratory chain performance in skeletal muscles [4]. Moreover, mitochondria from Mtln-knockout mice are more susceptible to membrane freeze-damage, and Mtln-knockout heart tissues show broad decreases in 22:6-containing lipids and increased cardiolipin damage/remodeling, with worse myocardial ischemia-reperfusion injury [3]. Loss of MTLN in mice also causes the accumulation of very long-chain fatty acids (VLCFAs) and protects against western diet/fructose-induced insulin-resistance [5].

In conclusion, Mtln is essential for maintaining normal oxidative metabolism, lipid metabolism, and mitochondrial function. Studies using Mtln knockout mouse models have revealed its role in obesity, kidney-related diseases, muscle function, and cardiac protection. Understanding Mtln's functions may provide insights into potential therapeutic targets for these related disease areas [1,2,3,4,5].

References:

1. Averina, Olga A, Permyakov, Oleg A, Emelianova, Mariia A, Vyssokikh, Mikhail Yu, Sergiev, Petr V. 2022. Mitochondrial peptide Mtln contributes to oxidative metabolism in mice. In Biochimie, 204, 136-139. doi:10.1016/j.biochi.2022.09.009. https://pubmed.ncbi.nlm.nih.gov/36174793/

2. Averina, Olga A, Permyakov, Oleg A, Emelianova, Mariia A, Vyssokikh, Mikhail Y, Sergiev, Petr V. 2023. Kidney-Related Function of Mitochondrial Protein Mitoregulin. In International journal of molecular sciences, 24, . doi:10.3390/ijms24109106. https://pubmed.ncbi.nlm.nih.gov/37240452/

3. Stein, Colleen S, Zhang, Xiaoming, Witmer, Nathan H, Shaikh, Saame Raza, Boudreau, Ryan L. 2024. Mitoregulin supports mitochondrial membrane integrity and protects against cardiac ischemia-reperfusion injury. In bioRxiv : the preprint server for biology, , . doi:10.1101/2024.05.31.596875. https://pubmed.ncbi.nlm.nih.gov/38853979/

4. Averina, Olga A, Permyakov, Oleg A, Emelianova, Mariia A, Vysokikh, Mikhail Yu, Sergiev, Petr V. 2023. Mitoregulin Contributes to Creatine Shuttling and Cardiolipin Protection in Mice Muscle. In International journal of molecular sciences, 24, . doi:10.3390/ijms24087589. https://pubmed.ncbi.nlm.nih.gov/37108753/

5. Zhang, Shan, Guo, Yabo, Fidelito, Gio, Stroud, David A, Ho, Lena. 2023. LINC00116-encoded microprotein mitoregulin regulates fatty acid metabolism at the mitochondrial outer membrane. In iScience, 26, 107558. doi:10.1016/j.isci.2023.107558. https://pubmed.ncbi.nlm.nih.gov/37664623/

6. Friesen, Max, Warren, Curtis R, Yu, Haojie, Rinn, John L, Cowan, Chad A. 2020. Mitoregulin Controls β-Oxidation in Human and Mouse Adipocytes. In Stem cell reports, 14, 590-602. doi:10.1016/j.stemcr.2020.03.002. https://pubmed.ncbi.nlm.nih.gov/32243843/

7. Chugunova, Anastasia, Loseva, Elizaveta, Mazin, Pavel, Sergiev, Petr, Dontsova, Olga. 2019. LINC00116 codes for a mitochondrial peptide linking respiration and lipid metabolism. In Proceedings of the National Academy of Sciences of the United States of America, 116, 4940-4945. doi:10.1073/pnas.1809105116. https://pubmed.ncbi.nlm.nih.gov/30796188/