Ren 2023 Cell Discov

Ren X, Yan J, Zhao Q, Bao X, Han X, Zheng C, Zhou Y, Chen L, Wang B, Yang L, Lin X, Liu D, Lin Y, Li M, Fang H, Lu Z, Lyu J (2023) The Fe-S cluster assembly protein IscU2 increases α-ketoglutarate catabolism and DNA 5mC to promote tumor growth. https://doi.org/10.1038/s41421-023-00558-8

» Cell Discov 9:76. PMID: 37488138 Open Access

Ren Xiaojun, Yan Jimei, Zhao Qiongya, Bao Xinzhu, Han Xinyu, Zheng Chen, Zhou Yan, Chen Lifang, Wang Bo, Yang Lina, Lin Xi, Liu Dandan, Lin Yuyan, Li Min, Fang Hezhi, Lu Zhimin, Lyu Jianxin (2023) Cell Discov

Abstract: IscU2 is a scaffold protein that is critical for the assembly of iron-sulfur (Fe-S) clusters and the functions of Fe-S-containing mitochondrial proteins. However, the role of IscU2 in tumor development remains unclear. Here, we demonstrated that IscU2 expression is much higher in human pancreatic ductal adenocarcinoma (PDAC) tissues than in adjacent normal pancreatic tissues. In PDAC cells, activated KRAS enhances the c-Myc-mediated IscU2 transcription. The upregulated IscU2 stabilizes Fe-S cluster and regulates the activity of tricarboxylic acid (TCA) cycle enzymes α-ketoglutarate (α-KG) dehydrogenase and aconitase 2, which promote α-KG catabolism through oxidative and reductive TCA cycling, respectively. In addition to promoting mitochondrial functions, activated KRAS-induced and IscU2-dependent acceleration of α-KG catabolism results in reduced α-KG levels in the cytosol and nucleus, leading to an increase in DNA 5mC due to Tet methylcytosine dioxygenase 3 (TET3) inhibition and subsequent expression of genes including DNA polymerase alpha 1 catalytic subunit for PDAC cell proliferation and tumor growth in mice. These findings underscore a critical role of IscU2 in KRAS-promoted α-KG catabolism, 5mC-dependent gene expression, and PDAC growth and highlight the instrumental and integrated regulation of mitochondrial functions and gene expression by IscU2 in PDAC cells.

• Bioblast editor: Plangger M

Labels: MiParea: Respiration  Pathology: Cancer 

Organism: Human  Tissue;cell: Islet cell;pancreas;thymus  Preparation: Intact cells 

Coupling state: LEAK, ROUTINE, ET 

HRR: Oxygraph-2k 

CN, 2023-08