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Mitochondrial UQCC3 Modulates Hypoxia Adaptation by Orchestrating OXPHOS and Glycolysis in Hepatocellular Carcinoma

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...

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Published in:Cell reports (Cambridge) 2020-11, Vol.33 (5), p.108340-108340, Article 108340
Main Authors: Yang, Yun, Zhang, Guimin, Guo, Fengzhu, Li, Qiqi, Luo, Hui, Shu, Yang, Shen, Yuge, Gan, Jia, Xu, Lin, Yang, Hanshuo
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Language:English
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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. [Display omitted] •UQCC3 is indispensable for bioenergetic reprogramming of HCC cells in hypoxia•UQCC3 is required for mitochondrial homeostasis and OXPHOS in hypoxia•Deficiency of UQCC3 impairs glycolysis and HIF-1α stabilization in hypoxia•UQCC3 and ROS generate positive feedback in hypoxia Yang et al. demonstrate that mitochondrial UQCC3 plays an indispensable role as HCC cells adapt to hypoxia. UQCC3 forms a positive feedback loop with mitochondrial ROS to sustain mitochondrial homeostasis, HIF-1α stabilization, and glycolytic activity in hypoxia and thus promotes bioenergetic reprogramming of HCC cells by simultaneously regulating OXPHOS and glycolysis.
ISSN:2211-1247
2211-1247
DOI:10.1016/j.celrep.2020.108340