Liu Benkun, Zhou Fucheng, Shi Bowen, Yan Yubo, Wang Yanbo, Wang Junfeng, Lang Yaoguo, Xu Shidong
Department of Thoracic Surgery, Harbin Medical University Cancer Hospital, No. 150, Haping Road, Nangang District, Harbin, 150081, Heilongjiang, China.
Invest New Drugs. 2025 May 22. doi: 10.1007/s10637-025-01545-4.
Mitochondrial dysfunction is a key driver of cancer progression, with therapies increasingly targeting metabolic weaknesses. Peptide YY (PYY), a gastrointestinal hormone, regulates cellular activity, but its influence on mitochondrial health in lung cancer remains poorly understood. We explored how PYY1-36, a bioactive fragment of PYY, affects mitochondrial stability in NCI-H1581 lung cancer cells. Using dose-response experiments, we measured oxidative stress by tracking lactate dehydrogenase (LDH) release, mitochondrial ROS levels, and oxidative DNA damage (8-OHdG). Energy production was evaluated through ATP levels, oxygen consumption rates (OCR), and Complex I activity. We also analyzed mitochondrial biogenesis markers (NRF1, TFAM, PGC-1α) and the RNA-binding protein RBM43 via qPCR and immunoblotting. Dose-dependent tests showed that PYY1-36 triggers mitochondrial oxidative damage, marked by higher LDH release and ROS spikes. These changes aligned with sharp drops in ATP production and disrupted respiratory function. Notably, PYY1-36 reduced mitochondrial mass and biogenesis, supported by weaker MitoTracker Red signals and lower mtDNA/nDNA ratios. Key regulators NRF1 and TFAM were strongly suppressed, pointing to widespread mitochondrial failure. Intriguingly, PYY1-36 blocked PGC-1α protein synthesis without altering mRNA levels, suggesting a post-transcriptional control mechanism. PYY1-36 also boosted RBM43 levels. Knocking down RBM43 reversed PYY1-36's effects on PGC-1α and mitochondrial health. Our findings reveal RBM43 as a central player in PYY1-36-induced mitochondrial dysfunction through its suppression of PGC-1α translation. Targeting RBM43 could unlock new strategies to tackle metabolic chaos in lung cancer.
线粒体功能障碍是癌症进展的关键驱动因素，治疗方法越来越多地针对代谢弱点。肽YY（PYY）是一种胃肠激素，可调节细胞活性，但其对肺癌线粒体健康的影响仍知之甚少。我们探讨了PYY的生物活性片段PYY1-36如何影响NCI-H1581肺癌细胞中的线粒体稳定性。通过剂量反应实验，我们通过追踪乳酸脱氢酶（LDH）释放、线粒体ROS水平和氧化性DNA损伤（8-OHdG）来测量氧化应激。通过ATP水平、氧消耗率（OCR）和复合物I活性评估能量产生。我们还通过qPCR和免疫印迹分析了线粒体生物发生标志物（NRF1、TFAM、PGC-1α）和RNA结合蛋白RBM43。剂量依赖性测试表明，PYY1-36引发线粒体氧化损伤，表现为LDH释放增加和ROS峰值升高。这些变化与ATP产生的急剧下降和呼吸功能紊乱一致。值得注意的是，PYY1-36降低了线粒体质量和生物发生，MitoTracker Red信号减弱和mtDNA/nDNA比率降低证明了这一点。关键调节因子NRF1和TFAM受到强烈抑制，表明存在广泛的线粒体功能衰竭。有趣的是，PYY1-36在不改变mRNA水平的情况下阻断了PGC-1α蛋白的合成，提示存在转录后控制机制。PYY1-36还提高了RBM43水平。敲低RBM43可逆转PYY1-36对PGC-1α和线粒体健康的影响。我们的研究结果表明，RBM43通过抑制PGC-1α翻译，在PYY1-36诱导的线粒体功能障碍中起核心作用。靶向RBM43可能会开启应对肺癌代谢紊乱的新策略。
