美国德克萨斯大学西南医学中心Ralph J. DeBerardinis和美国圣犹达儿童研究医院Min Ni共同合作，近期取得重要工作进展。他们研究提出，电子传递链抑制增加了细胞对嘌呤转运和回收的依赖性。相关研究成果2024年6月13日在线发表于《细胞—代谢》杂志上。

据介绍，线粒体包含许多稳态和生长所需的代谢途径。

为了探索人类细胞对线粒体功能障碍的反应，研究人员对患有各种线粒体疾病的患者和电子传递链（ETC）阻断的癌症细胞的成纤维细胞进行了代谢组学研究。

这些分析揭示了嘌呤代谢的广泛扰动，稳定同位素追踪表明，ETC缺陷抑制了嘌呤的从头合成，同时增强了嘌呤的回收。在人类肺癌中，具有低线粒体氧化代谢标志物的肿瘤表现出拯救酶次黄嘌呤磷酸核糖转移酶1（HPRT1）和HPRT1产物肌苷单磷酸的表达水平增强。

从机制上讲，ETC阻断激活戊糖磷酸途径，提供磷酸核糖基二磷酸，以驱动通过摄取细胞外碱基提供的嘌呤回收。阻断HPRT1使癌症细胞对ETC抑制敏感。

总之，这些发现证明了细胞如何在ETC阻断后重塑嘌呤代谢，并揭示了低呼吸肿瘤中新的代谢脆弱性。

附：英文原文

Title: Electron transport chain inhibition increases cellular dependence on purine transport and salvage

Author: Zheng Wu, Divya Bezwada, Feng Cai, Robert C. Harris, Bookyung Ko, Varun Sondhi, Chunxiao Pan, Hieu S. Vu, Phong T. Nguyen, Brandon Faubert, Ling Cai, Hongli Chen, Misty Martin-Sandoval, Duyen Do, Wen Gu, Yuanyuan Zhang, Yuannyu Zhang, Bailey Brooks, Sherwin Kelekar, Lauren G. Zacharias, K. Celeste Oaxaca, Joao S. Patricio, Thomas P. Mathews, Javier Garcia-Bermudez, Min Ni, Ralph J. DeBerardinis

Issue&Volume: 2024-06-13

Abstract: Mitochondria house many metabolic pathways required for homeostasis and growth. To explore how human cells respond to mitochondrial dysfunction, we performed metabolomics in fibroblasts from patients with various mitochondrial disorders and cancer cells with electron transport chain (ETC) blockade. These analyses revealed extensive perturbations in purine metabolism, and stable isotope tracing demonstrated that ETC defects suppress de novo purine synthesis while enhancing purine salvage. In human lung cancer, tumors with markers of low oxidative mitochondrial metabolism exhibit enhanced expression of the salvage enzyme hypoxanthine phosphoribosyl transferase 1 (HPRT1) and high levels of the HPRT1 product inosine monophosphate. Mechanistically, ETC blockade activates the pentose phosphate pathway, providing phosphoribosyl diphosphate to drive purine salvage supplied by uptake of extracellular bases. Blocking HPRT1 sensitizes cancer cells to ETC inhibition. These findings demonstrate how cells remodel purine metabolism upon ETC blockade and uncover a new metabolic vulnerability in tumors with low respiration.

DOI: 10.1016/j.cmet.2024.05.014

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(24)00190-6