RNA-Adjusted TUFM Protein State Captures Mitochondrial Proteome Organization in Lung Adenocarcinoma

Abstract Matched transcriptome-proteome measurements can reveal protein-state information not represented by RNA abundance. We integrated four lung adenocarcinoma (LUAD) proteogenomic cohorts, two longitudinal osimertinib transcriptomic systems, and DepMap CRISPR screens to test whether the TUFM protein captures coordinated mitochondrial proteome organization beyond TUFM RNA. In discovery LUAD, the RNA-adjusted TUFM protein state (TUFM_PT) added substantial explanatory information beyond its transcript for mitochondrial-translation and oxidative-phosphorylation (OXPHOS) protein programs. Across three independent cohorts (n = 292), TUFM_PT replicated with pooled Spearman rho values of 0.564 and 0.620 for mitochondrial translation and OXPHOS, respectively, and ranked 40th and 23rd among 5,242 externally benchmarked RNA-adjusted protein states. Associations persisted after copy-number, clinical, tumor-purity, and background-proteome adjustment. Highest-ranked human TUFM_PT proteomic partners were enriched in an independent CRISPR codependency network, including after the exclusion of prespecified mitochondrial genes, demonstrating cross-modal convergence at the network tail. Longitudinal osimertinib data provided complementary temporal context: early drug tolerance suppressed mitochondrial translation and OXPHOS transcripts, followed by later recovery without universal TUFM mRNA recovery. Together, these findings identify TUFM_PT as a reproducible, network-embedded proteomic readout of mitochondrial organization beyond TUFM RNA, while the longitudinal transcriptomes define the treatment-stage context rather than treatment-linked TUFM protein dynamics.