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Glutavnine Oxidation Maintains the TCA Cycle and Cell Survival during Impaired Mitochondrial Pyruvate Transport

机译:谷氨酰胺氧化可在线粒体丙酮酸运输受损期间维持TCA周期和细胞存活

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摘要

Alternative modes of metabolism enable cells to resist metabolic stress. Inhibiting these compensatory pathways may produce synthetic lethality. We previously demonstrated that glucose deprivation stimulated a pathway in which acetyl-CoA was formed from glutamine downstream of glutamate dehydroge-nase (GDH). Here we show that import of pyruvate into the mitochondria suppresses GDH and gluta-mine-dependent acetyl-CoA formation. Inhibiting the mitochondrial pyruvate carrier (MPC) activates GDH and reroutes glutamine metabolism to generate both oxaloacetate and acetyl-CoA, enabling persistent tricarboxylic acid (TCA) cycle function. Pharmacological blockade of GDH elicited largely cytostatic effects in culture, but these effects became cytotoxic when combined with MPC inhibition. Concomitant administration of MPC and GDH inhibitors significantly impaired tumor growth compared to either inhibitor used as a single agent. Together, the data define a mechanism to induce glutaminolysis and uncover a survival pathway engaged during compromised supply of pyruvate to the mitochondria.
机译:新陈代谢的替代模式使细胞能够抵抗新陈代谢的压力。抑制这些补偿途径可能产生合成杀伤力。我们以前证明葡萄糖剥夺刺激了一条途径,其中谷氨酸脱氢酶(GDH)下游谷氨酰胺形成乙酰辅酶A。在这里,我们显示了将丙酮酸盐导入线粒体可抑制GDH和谷氨酰胺依赖性乙酰辅酶A的形成。抑制线粒体丙酮酸载体(MPC)可以激活GDH并重新引导谷氨酰胺代谢以生成草酰乙酸和乙酰辅酶A,从而实现持久的三羧酸(TCA)循环功能。 GDH的药理学阻断作用在培养物中引起了很大的细胞抑制作用,但是当与MPC抑制作用结合时,这些作用变成细胞毒性的。与任何一种用作单一药物的抑制剂相比,MPC和GDH抑制剂的同时给药显着损害了肿瘤的生长。总之,数据定义了一种机制,可诱导谷氨酰胺分解并揭示在丙酮酸向线粒体供应受损期间参与的生存途径。

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