NDUFA4 is a component of respiratory chain-oxidative phosphorylation pathway. NDUFA4 is highly expressed in tumor tissues, but little is known about the function of NDUFA4 in head and neck paraganglioma (HNPGL). We examined NDUFA4 expression in tissues from 10 HNPGL patients and 6 controls using qRT-PCR and Western blotting. NDUFA4 knockdown PGL-626 cells were established by using lentivirus infection and puromycin screening. Cell viability, ATP production, lipid reactive oxygen species, and mitochondrial membrane potential assays were performed to investigate the ferroptotic effects in NDUFA4 deficiency HNPGL cancer cells. Xenograft mouse model was created to detect the synergetic antitumor action between NDUFA4 deficiency and Metformin. NDUFA4 was upregulated in tumor tissues of HNPGL patients. NDUFA4 knockdown impaired the assembly of mitochondrial respiratory chain complexes and decreased the production of ATP and reduced cancer cell viability. Mechanistically, NDUFA4 knockdown increased cell ferroptosis, which further promoted Metformin-induced ferroptosis in PGL-626 cells. Therefore, NDUFA4 deficiency enhanced Metformin-mediated inhibition of the HNPGL progression in mice. In conclusion, NDUFA4 promotes the progression of HNPGL, and NDUFA4 knockdown enhances Metformin-mediated inhibition of the HNPGL progression in a mouse model.

中文翻译：

---

NDUFA4 通过抑制铁死亡促进头颈部副神经节瘤的进展。

NDUFA4 是呼吸链氧化磷酸化途径的组成部分。NDUFA4在肿瘤组织中高表达，但对于NDUFA4在头颈副神经节瘤（HNPGL）中的功能知之甚少。我们使用 qRT-PCR 和蛋白质印迹检测了 10 名 HNPGL 患者和 6 名对照者组织中的 NDUFA4 表达。通过慢病毒感染和嘌呤霉素筛选建立NDUFA4敲低的PGL-626细胞。进行细胞活力、ATP 产生、脂质活性氧和线粒体膜电位测定，以研究 NDUFA4 缺乏的 HNPGL 癌细胞中的铁死亡效应。创建异种移植小鼠模型来检测 NDUFA4 缺陷和二甲双胍之间的协同抗肿瘤作用。NDUFA4 在 HNPGL 患者的肿瘤组织中表达上调。NDUFA4 敲低会损害线粒体呼吸链复合物的组装，减少 ATP 的产生并降低癌细胞的活力。从机制上讲，NDUFA4 敲低增加了细胞铁死亡，进一步促进了二甲双胍诱导的 PGL-626 细胞铁死亡。因此，NDUFA4 缺乏增强了二甲双胍介导的对小鼠 HNPGL 进展的抑制。总之，NDUFA4 促进 HNPGL 的进展，并且 NDUFA4 敲低增强了二甲双胍介导的小鼠模型中 HNPGL 进展的抑制。