Targeting NDUFS2-mediated mitochondrial hyperfunction disrupts energy homeostasis and Akt-mTOR signaling in NSCLC

This study investigates the role of NDUFS2 in non-small cell lung cancer (NSCLC). The bioinformatics analysis of The Cancer Genome Atlas (TCGA) elucidated upregulation of NDUFS2 expression in NSCLC tissues relative to normal counterparts, correlating with unfavorable clinicopathological parameters. The single-cell RNA sequencing data further show NDUFS2 enrichment within malignant cancer cell populations across diverse primary NSCLC tumors and their metastatic sites. Validation studies employing local patient tissues and various NSCLC cell types corroborated the increased NDUFS2 expression observed in cancerous cells. NDUFS2 silencing or knockout induced profound mitochondrial dysfunction, and curtailed NSCLC cell viability, proliferation, migration, and invasion. These adverse cellular outcomes were partially mitigated by exogenous glucose or the antioxidant N-acetylcysteine. Conversely, forced overexpression of NDUFS2 enhanced mitochondrial function and augmented malignant characteristics. NDUFS2 was identified as a positive regulator of Akt-mTOR signaling pathway. The in vivo xenograft models showed that AAV-mediated NDUFS2 knockdown suppressed primary NSCLC cell xenograft growth in nude mice. Analysis of xenograft tissues confirmed the molecular consequences observed in vitro, including ATP depletion, oxidative damage, proliferation inhibition, Akt-mTOR inactivation, and apoptosis induction. Together, NDUFS2 acts as an oncogenic driver in NSCLC that supports mitochondrial function, enhances malignant phenotypes, and promotes the Akt-mTOR pathway.