Mitochondrial UQCC3 Modulates Hypoxia Adaptation by Orchestrating OXPHOS and Glycolysis in Hepatocellular Carcinoma
Yun Yang,
Guimin Zhang,
Fengzhu Guo,
Qiqi Li,
Hui Luo,
Yang Shu,
Yuge Shen,
Jia Gan,
Lin Xu,
Hanshuo Yang
Affiliations
Yun Yang
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China
Guimin Zhang
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China
Fengzhu Guo
Lung Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
Qiqi Li
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China
Hui Luo
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China
Yang Shu
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China
Yuge Shen
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China
Jia Gan
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China
Lin Xu
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China
Hanshuo Yang
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China; Experimental and Research Animal Institute, Sichuan University, Chengdu, China; Corresponding author
Summary: 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.
