MRPS5 (mitochondrial ribosomal protein S5) is a structural component of the mitochondrial small ribosomal subunit essential for mitochondrial protein translation 1. As an RNA-binding protein localized to the mitochondrial inner membrane, MRPS5 directly participates in translating mtDNA-encoded oxidative phosphorylation (OXPHOS) proteins 2. MRPS5 functions as a critical regulator of mitonuclear communication, coordinating metabolic homeostasis during cellular stress. Loss of MRPS5 impairs mitochondrial translation and OXPHOS capacity, triggering an ATF4-mediated mitochondrial stress response 1. Paradoxically, reduced MRPS5 expression in cardiomyocytes promotes proliferation and cardiac regeneration through ATF4-dependent upregulation of KNL1, improving cardiac function after myocardial infarction 1. Conversely, complete developmental loss causes embryonic lethality, while postnatal loss induces cardiac hypertrophy and heart failure via dysregulation of the Klf15 metabolic pathway 2. Beyond cardiac function, MRPS5 serves as an aging-associated marker 3 and regulates metabolic reprogramming in liver cancer stem cells through SIRT1-mediated acetylation, controlling the balance between mitochondrial respiration and glycolytic metabolism 4. MRPS5 variants influence disease susceptibility, including leprosy susceptibility in Chinese populations 5 and noise-induced hearing loss through effects on mitoribosomal translation accuracy 6. MRPS5 is incorporated into prognostic signatures for hepatocellular carcinoma prognosis and sorafenib sensitivity 7, and correlates with immune infiltration patterns in acute myocardial infarction 8.