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<p>NSCLC remains a primary contributor to cancer-related mortality. This study comprehensively elucidates the expression and the functional role of NDUFA9 in NSCLC pathogenesis. Our initial bioinformatic analyses, drawing from TCGA and single-cell RNA sequencing data, revealed a significant upregulation of <i>NDUFA9</i> expression within NSCLC tumor tissues and cancer cell populations, correlating with unfavorable clinicopathological indicators, including advanced pathological T stage, male gender, smoking history, and diminished overall survival. Furthermore, NDUFA9 was distinctly enriched in proliferating cancer cells and malignant epithelial cells across diverse metastatic sites. Experimental validation confirmed NDUFA9’s heightened mRNA and protein expression in both locally-treated NSCLC patient tissues and various NSCLC cell types. Functionally, NDUFA9 shRNA or knockout compromised mitochondrial function in NSCLC cells. This impairment was evidenced by a reduced oxygen consumption rate, diminished mitochondrial complex I activity, decreased ATP production, mitochondrial depolarization, reduced mtDNA contents, and an augmented generation of ROS. Concomitantly, NDUFA9 depletion significantly suppressed key malignant phenotypes, including cell proliferation and migration, while inducing apoptosis in NSCLC cells. Conversely, NDUFA9 overexpression in NSCLC cells enhanced mitochondrial function and promoted malignant cellular phenotypes. NDUFA9 was identified as a positive regulator of the Akt-mTOR signaling pathway; its depletion inhibited, and its overexpression enhanced, mTOR kinase activity and the phosphorylation of Akt and S6K in primary NSCLC cells. Bioinformatics predictions, subsequently validated experimentally, established YY1 as a pivotal transcription factor directly binding to and upregulating NDUFA9 expression in NSCLC tissues and cells. Finally, in vivo xenograft studies demonstrated that NDUFA9 silencing suppressed tumor growth, corroborating the in vitro findings by inhibiting mitochondrial function, proliferation, Akt-mTOR activation, and inducing apoptosis within tumor tissues. Thus, NDUFA9 is a crucial regulator of mitochondrial metabolism and malignant progression in NSCLC, driven by YY1-mediated transcriptional control.</p>

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YY1-mediated NDUFA9 upregulation promotes NSCLC cell growth through mitochondrial and Akt-mTOR pathway modulation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月21日

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  • Yubo Yan,
  • Yuge Zhao,
  • Jun Tang,
  • Xiwen Wang,
  • Jungang Zhao,
  • Yingnan Yang

摘要

NSCLC remains a primary contributor to cancer-related mortality. This study comprehensively elucidates the expression and the functional role of NDUFA9 in NSCLC pathogenesis. Our initial bioinformatic analyses, drawing from TCGA and single-cell RNA sequencing data, revealed a significant upregulation of NDUFA9 expression within NSCLC tumor tissues and cancer cell populations, correlating with unfavorable clinicopathological indicators, including advanced pathological T stage, male gender, smoking history, and diminished overall survival. Furthermore, NDUFA9 was distinctly enriched in proliferating cancer cells and malignant epithelial cells across diverse metastatic sites. Experimental validation confirmed NDUFA9’s heightened mRNA and protein expression in both locally-treated NSCLC patient tissues and various NSCLC cell types. Functionally, NDUFA9 shRNA or knockout compromised mitochondrial function in NSCLC cells. This impairment was evidenced by a reduced oxygen consumption rate, diminished mitochondrial complex I activity, decreased ATP production, mitochondrial depolarization, reduced mtDNA contents, and an augmented generation of ROS. Concomitantly, NDUFA9 depletion significantly suppressed key malignant phenotypes, including cell proliferation and migration, while inducing apoptosis in NSCLC cells. Conversely, NDUFA9 overexpression in NSCLC cells enhanced mitochondrial function and promoted malignant cellular phenotypes. NDUFA9 was identified as a positive regulator of the Akt-mTOR signaling pathway; its depletion inhibited, and its overexpression enhanced, mTOR kinase activity and the phosphorylation of Akt and S6K in primary NSCLC cells. Bioinformatics predictions, subsequently validated experimentally, established YY1 as a pivotal transcription factor directly binding to and upregulating NDUFA9 expression in NSCLC tissues and cells. Finally, in vivo xenograft studies demonstrated that NDUFA9 silencing suppressed tumor growth, corroborating the in vitro findings by inhibiting mitochondrial function, proliferation, Akt-mTOR activation, and inducing apoptosis within tumor tissues. Thus, NDUFA9 is a crucial regulator of mitochondrial metabolism and malignant progression in NSCLC, driven by YY1-mediated transcriptional control.