State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China.
Lung Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
Cell Rep. 2020 Nov 3;33(5):108340. doi: 10.1016/j.celrep.2020.108340.
Bioenergetic reprogramming during hypoxia adaption is critical to promote hepatocellular carcinoma (HCC) growth and progression. However, the mechanism underlying the orchestration of mitochondrial OXPHOS (oxidative phosphorylation) and glycolysis in hypoxia is not fully understood. Here, we report that mitochondrial UQCC3 (C11orf83) expression increases in hypoxia and correlates with the poor prognosis of HCC patients. Loss of UQCC3 impairs HCC cell proliferation in hypoxia in vitro and in vivo. Mechanistically, UQCC3 forms a positive feedback loop with mitochondrial reactive oxygen species (ROS) to sustain UQCC3 expression and ROS generation in hypoxic HCC cells and subsequently maintains mitochondrial structure and function and stabilizes HIF-1α expression to enhance glycolysis under hypoxia. Thus, UQCC3 plays an indispensable role for bioenergetic reprogramming of HCC cells during hypoxia adaption by simultaneously regulating OXPHOS and glycolysis. The positive feedback between UQCC3 and ROS indicates a self-modulating model within mitochondria that initiates the adaptation of HCC to hypoxic stress.
在低氧适应过程中进行生物能量重编程对于促进肝细胞癌 (HCC) 的生长和进展至关重要。然而，低氧条件下线粒体 OXPHOS（氧化磷酸化）和糖酵解协调的机制尚不完全清楚。在这里，我们报告在线粒体 UQCC3（C11orf83）在低氧条件下表达增加，并与 HCC 患者的不良预后相关。UQCC3 的缺失会损害 HCC 细胞在低氧条件下的体外和体内增殖。在机制上，UQCC3 与线粒体活性氧 (ROS) 形成正反馈回路，以维持低氧 HCC 细胞中 UQCC3 的表达和 ROS 的产生，随后维持线粒体结构和功能，并稳定 HIF-1α 的表达，以增强低氧条件下的糖酵解。因此，UQCC3 通过同时调节 OXPHOS 和糖酵解，在 HCC 细胞适应低氧过程中对其生物能量重编程起着不可或缺的作用。UQCC3 和 ROS 之间的正反馈表明线粒体内部存在一种自我调节模型，该模型启动了 HCC 对低氧应激的适应。
