A compendium of co-regulated mitoribosomal proteins in pan-cancer uncovers collateral defective events in tumor malignancy

Mitochondria are major organelles responsible for cellular energy and metabolism, and their dysfunction is tightly linked to cancer. The mitochondrial ribosome (mitoribosome) is a protein complex consisting of 82 mitoribosomal proteins (MRPs) encoded by nuclear genes and is essential for mitochondrial protein synthesis. However, their roles in tumorigenesis remain poorly understood. We performed pan-cancer analyses of 18,177 tumors representing 28 cancer types to determine somatic alterations of MRP genes as a genetic basis for tumorigenesis. We identified a set of 20 altered MRPs known to be involved in early assembly of the mitoribosome complex. We found that tumors with affected MRPs were associated with impaired mitochondrial functions and TP53 mutations accompanied by increased genomic instability and intra-tumor heterogeneity. MRP deletions were associated with poor survival. Our results reveal a key role for mitochondrial ribosome biogenesis in tumor malignancy across cancer types.