MRPL39 is a mitochondrial ribosomal protein that comprises one of 52 proteins in the large subunit of the mitochondrial ribosome (mitoribosome) 1. As a core component of the mitoribosome, MRPL39 participates in synthesizing the 13 subunits of the mitochondrial oxidative phosphorylation (OXPHOS) system encoded by mitochondrial DNA 1. The protein is essential for proper mitoribosomal assembly, with structural studies indicating its involvement in late-stage biogenesis through RNA-protein interactions 2. Pathogenic biallelic variants in MRPL39 cause combined oxidative phosphorylation deficiency 59, manifesting as pediatric-onset mitochondrial disease with variable severity, ranging from lethal infantile-onset Leigh syndrome to milder forms with adult survival 1. Disease variants impair large mitoribosomal subunit stability and function, reducing OXPHOS complex abundance 1. Quantitative proteomics effectively identifies these defects, offering diagnostic utility for exome-unsolved mitochondrial disease patients 1. Clinically, MRPL39 dysfunction requires early recognition in critically ill infants presenting with multisystem disease, as ultrarapid genomic diagnosis can guide management decisions including potential palliative care redirection 3. Beyond inherited mitochondrial disease, an lncRNA designated lnc-MRPL39-2:1 has been implicated in nasopharyngeal carcinoma tumorigenesis through HuR-mediated stabilization of β-catenin mRNA 4, highlighting potential pleiotropic effects of MRPL39-derived transcripts in cancer biology.