PDF(Pubmed)
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.
摘要：
线粒体拥有体内平衡和生长所需的许多代谢途径。探索人类细胞对线粒体功能障碍的反应，我们在各种线粒体疾病患者的成纤维细胞和电子传递链(ETC)阻断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扰动，稳定同位素示踪表明，ETC缺陷抑制嘌呤从头合成，同时增强嘌呤补救。在人类肺癌中，具有低氧化线粒体代谢标志物的肿瘤表现出补救酶次黄嘌呤磷酸核糖基转移酶1（HPRT1）和高水平的HPRT1产物单磷酸肌苷的表达增强。机械上,ETC阻断激活磷酸戊糖途径，提供磷酸核糖二磷酸来驱动通过摄取细胞外碱基提供的嘌呤补救。阻断HPRT1使癌细胞对ETC抑制敏感。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的新代谢脆弱性。
