Mtx2, encoding Metaxin-2, is an outer mitochondrial membrane protein. It is involved in maintaining mitochondrial cristae architecture, which is crucial for preventing mitochondrial DNA (mtDNA) release and subsequent activation of the type I interferon (IFN-I) response via the cGAS-STING pathway [1]. It also plays roles in various cellular processes and is associated with multiple disease-related pathways.

Loss-of-function studies have provided significant insights. Conditional podocyte-specific Mtx2 knockout (Pod-Mtx2-KO) mice showed podocyte and glomerular abnormalities, including microalbuminuria, glomerular mesangial hyperplasia, and foot process fusion. MTX2 deficiency led to abnormal mitochondrial structure and dysfunction in podocytes, affecting their adhesion, migration, and endocytosis [2]. In mouse liver, knocking out MTX2 induced a robust STING-dependent IFN-I response, highlighting its role in preventing inflammation [1]. In zebrafish, morpholino knockdown of Mtx2 caused stalling of epiboly due to yolk rupture, indicating its role in regulating microfilament formation and morphogenetic movements during development [3]. Also, in patients, null mutations in MTX2 cause mandibuloacral dysplasia, a progeroid syndrome characterized by growth retardation, bone resorption, and other multisystem manifestations [4,5,6].

In conclusion, Mtx2 is essential for maintaining mitochondrial structure and function, as well as for normal cellular and developmental processes. Gene knockout models, especially in mice, have been crucial in revealing its role in diseases such as glomerulopathy, inflammation-related disorders, and progeroid syndromes. These findings enhance our understanding of the molecular mechanisms underlying these diseases and may offer potential therapeutic targets.

References:

1. He, Baiyu, Yu, Huatong, Liu, Shanshan, Liu, Qinghua, Jiang, Hui. . Mitochondrial cristae architecture protects against mtDNA release and inflammation. In Cell reports, 41, 111774. doi:10.1016/j.celrep.2022.111774. https://pubmed.ncbi.nlm.nih.gov/36476853/

2. Li, Ting, Bao, Ying, Xia, Yu, Jiang, Pingping, Mao, Jianhua. 2024. Loss of MTX2 causes mitochondrial dysfunction, podocyte injury, nephrotic proteinuria and glomerulopathy in mice and patients. In International journal of biological sciences, 20, 937-952. doi:10.7150/ijbs.89916. https://pubmed.ncbi.nlm.nih.gov/38250156/

3. Wilkins, Simon J, Yoong, Simon, Verkade, Heather, Heath, Joan K, Perkins, Andrew C. 2007. Mtx2 directs zebrafish morphogenetic movements during epiboly by regulating microfilament formation. In Developmental biology, 314, 12-22. doi:. https://pubmed.ncbi.nlm.nih.gov/18154948/

4. Fu, Xiaohui, Chen, Shuli, Huang, Xiao, Lin, Weinan, Yang, Qin. 2024. Case report: A novel splice-site mutation of MTX2 gene caused mandibuloacral dysplasia progeroid syndrome: the first report from China and literature review. In Frontiers in endocrinology, 15, 1345067. doi:10.3389/fendo.2024.1345067. https://pubmed.ncbi.nlm.nih.gov/38544690/

5. Elouej, Sahar, Harhouri, Karim, Le Mao, Morgane, Lévy, Nicolas, De Sandre-Giovannoli, Annachiara. 2020. Loss of MTX2 causes mandibuloacral dysplasia and links mitochondrial dysfunction to altered nuclear morphology. In Nature communications, 11, 4589. doi:10.1038/s41467-020-18146-9. https://pubmed.ncbi.nlm.nih.gov/32917887/

6. Yeter Doğan, Burcu, Günay, Neslihan, Ada, Yasin, Doğan, Muhammet Ensar. 2022. A novel MTX2 gene splice site variant resulting in exon skipping, causing the recently described mandibuloacral dysplasia progeroid syndrome. In American journal of medical genetics. Part A, 191, 173-182. doi:10.1002/ajmg.a.63010. https://pubmed.ncbi.nlm.nih.gov/36269149/