MRPS25 encodes a structural component of the 28S small subunit of the mitochondrial ribosome, essential for mitochondrial protein synthesis. 1 As a nuclear-encoded mitochondrial ribosomal protein, MRPS25 is required for proper assembly and function of the mitochondrial translation machinery. 2 The protein facilitates inter-protein contacts within the ribosomal subunit; mutations disrupting these interactions impair 28S subunit assembly and substantially reduce mitochondrial translation efficiency. 1 MRPS25 dysfunction results in compromised ATP production and mitochondrial dysfunction. 2 Pathogenic variants cause combined oxidative phosphorylation deficiency, manifesting as encephalomyopathy with dyskinetic cerebral palsy, corpus callosum abnormalities, and mitochondrial myopathy characterized by decreased respiratory chain subunit levels. 1 Recent network analysis identified MRPS25 as a downregulated hub gene in heart failure with high diagnostic potential (AUC > 0.8), suggesting broader cardiovascular relevance beyond its classical mitochondrial translation role. 3 The minimal functional redundancy among mitochondrial ribosomal proteins indicates that MRPS25 deficiency cannot be compensated by other MRP family members, making it critical for maintaining adequate cellular energy metabolism throughout development and adult life.