铁硫蛋白参与了氧化磷酸化（OXPHOS）和三羧酸循环等关键过程，其辅基铁硫簇2Fe-2S/4Fe-4S的组装依赖于IscU2。有研究分别报道在多种肿瘤细胞中IscU2呈低表达，OXPHOS复合体的组装与其复合体亚基铁硫蛋白的表达相关，肿瘤细胞中OXPHOS功能普遍降低而糖酵解增强。我们的研究发现IscU2下调可导致OXPHOS功能缺陷，而OXPHOS功能缺陷可激活细胞核-线粒体逆向信号转导重编程细胞的代谢方式。因此，我们认为：线粒体IscU2作为起始节点，通过下调OXPHOS功能，激活逆向信号转导，介导肿瘤细胞代谢重编程，促进肿瘤生长。基于此，本项目拟以线粒体IscU2影响铁硫簇组装为切入点，通过OXPHOS功能检测揭示IscU2在肿瘤细胞代谢重编程中的作用，进一步验证IscU2通过下调OXPHOS功能激活逆向信号转导实现细胞代谢重编程的机制，阐明铁硫簇组装与肿瘤发生的关系。

IscU2 is necessary for mitochondrial biogenesis due to its essential role in the iron-sulfur assemble of several iron-sulfur proteins within oxidative phosphorylation system (OXPHOS). In cancer cells, the shift of metabolic profile from OXPHOS to glycolysis was regulated by oncogene and tumor suppressor genes such as P53, RAS and mTOR, through which, a translational or post-translational modification of IscU2 was induced in cancer cells to decrease OXPHOS. Therefore, IscU2 was considered as a final executive protein targeted to OXPHOS in the process of metabolic reprogramming. In our preliminary work, we found that decreased level of IscU2 impaired OXPHOS function, and decreased OXPHOS function activates mitochondrial-mediated signaling pathways (retrograde signaling pathways/mitochondrial-nuclear interaction) such as AMPK, AKT, JNK, and P38, which are key mediators of metabolic reprogramming in cancer cells. Under this situation, it is likely that IscU2 serves as an upstream regulator rather than a downstream executive protein in metabolic network. To uncover the underlying mechanism of IscU2 in the metabolic reprogramming of cancer cells through retrograde signaling pathways. We are planning to build a network of metabolic profiles and retrograde signaling pathways through high-throughput technology in cell models with different expression of IscU2 or its target protein; find out target protein of IscU2 and downstream signals of OXPHOS dysfunction, which can initiate metabolic related retrograde signaling pathways. We expect that our proposed research will provide important and previously unrevealed mechanisms of metabolic reprogramming in cancer cells.