MTX2 encodes Metaxin-2, an outer mitochondrial membrane protein that functions as a component of the SAM (Sorting and Assembly Machinery) complex involved in mitochondrial protein transport and cristae organization 1. MTX2 works in conjunction with Metaxin-1 (MTX1) to maintain mitochondrial structure and function, and its loss leads to mitochondrial dysfunction including network fragmentation, oxidative phosphorylation impairment, and abnormal cristae architecture 2. The protein is critical for preventing mitochondrial DNA release into the cytosol, which would otherwise activate the cGAS-STING inflammatory pathway 13. MTX2 stability is regulated through deubiquitination by USP10, which removes K48-linked ubiquitin chains at lysine 93 3. Homozygous null mutations in MTX2 cause mandibuloacral dysplasia progeroid syndrome (MADaM), a severe premature aging disorder characterized by growth retardation, bone abnormalities, lipodystrophy, and multisystem involvement including cardiovascular and renal complications 245. MTX2 deficiency also causes podocyte dysfunction and nephrotic proteinuria through impairment of the Sam50-CHCHD3-Mitofilin axis in the mitochondrial intermembrane space bridging complex 6. The protein's role in maintaining mitochondrial integrity makes it essential for cellular homeostasis and prevention of premature aging phenotypes.