MRPL47 deficiency drives mitochondrial dysfunction via ROS-p38-p21 signaling in non-small cell lung cancer.

Mitoribosomes are pivotal for cellular energy metabolism through the synthesis of proteins essential for the oxidative phosphorylation system. Although mitoribosomal dysregulation has been implicated in cancer, the genomic landscape of mitoribosomal proteins (MRPs) in nonsmall cell lung cancer (NSCLC) remains largely uncharacterized. In this study, we conducted a comprehensive analysis of expression, copy number variations, and mutations of MRPs using data from TCGA-NSCLC patients. This screen identified MRPL47 as a significantly amplified and overexpressed mitoribosomal gene in NSCLC. Validation across three independent datasets (n = 1513) confirmed MRPL47 as a robust and independent prognostic marker for poor survival. Functionally, MRPL47 inhibition significantly reduced NSCLC cell proliferation and migration. Intriguingly, MRPL47 depletion selectively impaired the translation of a subset of mitochondrial proteins, rather than causing a global defect, leading to impaired assembly of electron transport chain Complexes I and III. This resulted in a defective oxidative phosphorylation system, characterized by decreased ATP synthesis and elevated mitochondrial reactive oxygen species (ROS) levels. Transcriptomic analysis revealed a significant downregulation of E2F pathway activity in MRPL47-knockdown cells, with MRPL47 expression correlating with E2F target gene expression at both RNA and protein levels. Mechanistically, MRPL47 knockdown induced ROS accumulation, which promoted p38 phosphorylation and subsequent upregulation of p21. Increased p21, in turn, led to Rb hypophosphorylation, thereby inhibiting E2F activity and inducing G1 cell cycle arrest and senescence. Altogether, these findings establish that MRPL47 is amplified and overexpressed in NSCLC, functions as a strong prognostic predictor, and critically promotes tumor progression by modulating mitochondrial function and the ROS-p38-p21-Rb-E2F signaling axis.