Ali Md Yousuf, Griguer Corinne E, Flor Susanne, Oliva Claudia R
Interdisciplinary Graduate Program in Human Toxicology, The University of Iowa, Iowa City, IA 52242, USA.
Free Radical & Radiation Biology Program, Department of Radiation Oncology, The University of Iowa, Iowa City, IA 52242, USA.
Antioxidants (Basel). 2023 Feb 1;12(2):349. doi: 10.3390/antiox12020349.
Median overall survival is very low in patients with glioblastoma (GBM), largely because these tumors become resistant to therapy. Recently, we found that a decrease in the cytosolic labile iron pool underlies the acquisition of radioresistance. Both cytosolic and mitochondrial iron are important for regulating ROS production, which largely facilitates tumor progression and response to therapy. Here, we investigated the role of the mitochondrial iron transporters mitoferrin-1 (MFRN1) and mitoferrin-2 (MFRN2) in GBM progression. Analysis of The Cancer Genome Atlas database revealed upregulation of MFRN1 mRNA and downregulation of MFRN2 mRNA in GBM tumor tissue compared with non-GBM tissue, yet only the tumor expression level of MFRN1 mRNA negatively correlated with overall survival in patients. Overexpression of MFRN1 in glioma cells significantly increased the level of mitochondrial iron, enhanced the proliferation rate and anchorage-independent growth of these cells, and significantly decreased mouse survival in an orthotopic model of glioma. Finally, MFRN1 overexpression stimulated the upregulation of glutathione, which protected glioma cells from 4-hydroxynonenal-induced protein damage. Overall, these results demonstrate a mechanistic link between MFRN1-mediated mitochondrial iron metabolism and GBM progression. Manipulation of MFRN1 may provide a new therapeutic strategy for improving clinical outcomes in patients with GBM.
胶质母细胞瘤（GBM）患者的中位总生存期非常短，这主要是因为这些肿瘤会对治疗产生抗性。最近，我们发现胞质不稳定铁池的减少是获得放射抗性的基础。胞质铁和线粒体铁对于调节活性氧（ROS）的产生都很重要，而ROS的产生在很大程度上促进了肿瘤进展和对治疗的反应。在此，我们研究了线粒体铁转运蛋白铁转运蛋白1（MFRN1）和铁转运蛋白2（MFRN2）在GBM进展中的作用。对癌症基因组图谱数据库的分析显示，与非GBM组织相比，GBM肿瘤组织中MFRN1 mRNA上调，MFRN2 mRNA下调，但只有MFRN1 mRNA的肿瘤表达水平与患者的总生存期呈负相关。在胶质瘤细胞中过表达MFRN1可显著提高线粒体铁水平，增强这些细胞的增殖率和非锚定依赖性生长，并显著降低胶质瘤原位模型中小鼠的生存期。最后，MFRN1过表达刺激了谷胱甘肽的上调，从而保护胶质瘤细胞免受4-羟基壬烯醛诱导的蛋白质损伤。总体而言，这些结果证明了MFRN1介导的线粒体铁代谢与GBM进展之间的机制联系。对MFRN1的调控可能为改善GBM患者的临床结局提供一种新的治疗策略。
