MRPL49 (mitochondrial ribosomal protein L49) is a structural component of the mitochondrial large ribosomal subunit (39S) essential for mitochondrial translation and oxidative phosphorylation 1. The protein functions as part of the ribosomal machinery that synthesizes mitochondrially-encoded OXPHOS subunits, with direct interactions with co-translational insertion factors like Oxa1L at the mitochondrial inner membrane 2. MRPL49 is also subject to proteolytic processing by mitochondrial proteases, including neprilysin, which may regulate its function during mitochondrial stress 3. Pathogenic bi-allelic MRPL49 variants cause Combined Oxidative Phosphorylation Deficiency 60 (COXPD60), characterized by reduced levels of mitochondrial ribosomal subunits and decreased OXPHOS complex I and IV assembly 1. Clinical presentations are highly variable, ranging from Perrault syndrome (sensorineural hearing loss and ovarian insufficiency) to severe leukodystrophy, microcephaly, learning disability, and retinal dystrophy 1. MRPL49 dysfunction represents a key node in mitochondrial-immune regulatory networks, with downregulation associated with systemic diseases involving bioenergetic failure 4. The gene also emerges as a prognostic risk factor in acute myeloid leukemia through miRNA-mediated regulation 5. These findings underscore MRPL49's critical role in maintaining mitochondrial protein synthesis and cellular energetics across multiple organ systems.