MRPS5 is a mitochondrial ribosomal protein that functions as a structural component of the mitochondrial small ribosomal subunit and is essential for mitochondrial protein translation. It plays a critical role in maintaining mitochondrial oxidative phosphorylation (OXPHOS) and regulating mitonuclear communication—the signaling pathway between mitochondria and nucleus that coordinates cellular metabolism and stress responses. In cardiac physiology, MRPS5 exhibits context-dependent effects. Heterozygous loss of MRPS5 in mice activates the ATF4-mediated mitochondrial stress response, promoting cardiomyocyte proliferation and cardiac regeneration following myocardial infarction 1. Conversely, complete loss of MRPS5 during development causes cardiac defects and embryonic lethality, while postnatal loss induces cardiac hypertrophy and heart failure through impaired mitochondrial function and disrupted expression of the metabolic regulator Klf15 2. In liver cancer stem cells, MRPS5 undergoes acetylation-mediated subcellular redistribution controlled by the NAD+-dependent deacetylase SIRT1; deacetylated mitochondrial MRPS5 promotes complex-I function and NAD+ production, while acetylated nuclear MRPS5 increases glycolytic gene expression 3. In clear cell renal carcinoma, low MRPS5 expression correlates with poor overall survival and recurrence-free survival and serves as an independent prognostic biomarker 4. MRPS5 variants have been associated with genetic susceptibility to leprosy in Chinese populations 5 and with mitoribosomal mistranslation, leading to noise-induced hearing damage and anxiety-related behavioral alterations in mice 6. These findings position MRPS5 as a key regulator of mitochondrial function with therapeutic relevance in cardiac regeneration and cancer metabolism.