Electron transport chain inhibition increases cellular dependence on purine transport and salvage.

Cell metabolism Pub Date : 2024-07-02 Epub Date: 2024-06-13 DOI:10.1016/j.cmet.2024.05.014
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
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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.

Abstract Image

电子运输链抑制增加了细胞对嘌呤运输和挽救的依赖。
线粒体容纳了许多平衡和生长所需的代谢途径。为了探索人体细胞如何应对线粒体功能障碍,我们在患有各种线粒体疾病的成纤维细胞和电子传递链(ETC)受阻的癌细胞中进行了代谢组学研究。这些分析揭示了嘌呤代谢的广泛紊乱,稳定同位素追踪证明,ETC缺陷抑制了嘌呤的从头合成,同时加强了嘌呤的挽救。在人类肺癌中,具有线粒体低氧化代谢标志物的肿瘤表现出嘌呤挽救酶次黄嘌呤磷酸核糖转移酶1(HPRT1)的表达增强,以及HPRT1产物单磷酸肌苷的高水平。从机理上讲,ETC 阻断会激活磷酸戊糖途径,提供二磷酸磷酸核糖以驱动通过摄取细胞外碱基提供的嘌呤挽救。阻断 HPRT1 可使癌细胞对 ETC 抑制敏感。这些发现证明了细胞在 ETC 受阻后如何重塑嘌呤代谢,并揭示了呼吸作用低下的肿瘤在代谢方面的新弱点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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