胞浆
线粒体
脂肪生成
氧化应激
异柠檬酸脱氢酶
氧化磷酸化
IDH1
生物化学
柠檬酸合酶
化学
柠檬酸循环
生物
细胞生物学
新陈代谢
酶
突变
基因
作者
Wenting Dai,Zhichao Wang,Guan Wang,Qiong A. Wang,Ralph J DeBerardinis,Lei Jiang
标识
DOI:10.1101/2023.03.14.532533
摘要
Fatty acid synthase (FASN) maintains de novo lipogenesis (DNL) to support rapid growth in most proliferating cancer cells. Lipogenic acetyl CoA is primarily produced from carbohydrates but can arise from glutamine-dependent reductive carboxylation under hypoxia. Here we show that reductive carboxylation also occurs in the absence of DNL in cells with defective FASN. In this state, reductive carboxylation was mainly catalyzed by isocitrate dehydrogenase-1 (IDH1) in the cytosol, but IDH1-generated citrate was not used for DNL. Metabolic flux analysis (MFA) revealed that FASN deficiency induced a net cytosol-to-mitochondria citrate flux through citrate transport protein (CTP). A similar pathway was previously shown to mitigate detachment induced mitochondrial reactive oxygen species (mtROS) in anchorage-independent tumor spheroids. We further demonstrate that FASN deficient cells acquire resistance to oxidative stress in a CTP- and IDH1 dependent manner. Together with the reduced FASN activity in tumor spheroids, these data indicate that anchorage-independent malignant cells trade FASN-supported rapid growth for a cytosol-to-mitochondria citrate flux to gain redox capacity against detachment-induced oxidative stress.
科研通智能强力驱动
Strongly Powered by AbleSci AI