MCU-induced mitochondrial calcium uptake promotes mitochondrial biogenesis and colorectal cancer growth

Yang Liu,Yaya Wang,Jinliang Xing,Chao Jin,Tingting Ren,Xiaoying Ji,Mingpeng Jin,Rui Tan,Jianjun Zhu,Jing Zhao,Yongfeng Jia

doi:10.1038/s41392-020-0155-5

Abstract

Mitochondrial calcium uniporter (MCU) has an important role in regulating mitochondrial calcium (Ca2+) homeostasis. Dysregulation of mitochondrial Ca2+ homeostasis has been implicated in various cancers. However, it remains unclear whether MCU regulates mitochondrial Ca2+ uptake to promote cell growth in colorectal cancer (CRC). Therefore, in the present study the expression of MCU in CRC tissues and its clinical significance were examined. Following which, the biological function of MCU-mediated mitochondrial Ca2+ uptake in CRC cell growth and the underlying mechanisms were systematically evaluated using in in vitro and in vivo assays, which included western blotting, cell viability and apoptosis assays, as well as xenograft nude mice models. Our results demonstrated that MCU was markedly upregulated in CRC tissues at both the mRNA and protein levels. Upregulated MCU was associated with poor prognosis in patients with CRC. Our data reported that upregulation of MCU enhanced the mitochondrial Ca2+ uptake to promote mitochondrial biogenesis, which in turn facilitated CRC cell growth in vitro and in vivo. In terms of the underlying mechanism, it was identified that MCU-mediated mitochondrial Ca2+ uptake inhibited the phosphorylation of transcription factor A, mitochondrial (TFAM), and thus enhanced its stability to promote mitochondrial biogenesis. Furthermore, our data indicated that increased mitochondrial Ca2+ uptake led to increased mitochondrial production of ROS via the upregulation of mitochondrial biogenesis, which subsequently activated NF-κB signaling to accelerate CRC growth. In conclusion, the results indicated that MCU-induced mitochondrial Ca2+ uptake promotes mitochondrial biogenesis by suppressing phosphorylation of TFAM, thus contributing to CRC cell growth. Our findings reveal a novel mechanism underlying mitochondrial Ca2+-mediated CRC cell growth and may provide a potential pharmacological target for CRC treatment.

Highlights

Colorectal cancer (CRC) represents a huge public health burden worldwide and has higher rates of incidence in developed countries.[1]
Our data increased mitochondrial biogenesis in colorectal cancer (CRC) tumorigenesis.[14,15] revealed that Mitochondrial calcium uniporter (MCU) was markedly upregulated in the majority of we further explored the correlation between the CRC tissues at both the mRNA and protein levels compared with expression of MCU and mitochondrial biogenesis in CRC cells
Previous studies indicated that mitochondrial Ca2+ entry regulated by the MCU complex is closely associated with cancer progression, with remarkably different underlying mechanisms depending on the type and stage of cancer

Summary

Introduction

Colorectal cancer (CRC) represents a huge public health burden worldwide and has higher rates of incidence in developed countries.[1] Every year, CRC leads to the death of nearly 700,000 individuals, making it one of the most deadly cancers.[1] there has been progress in the early diagnosis and treatment of CRC, the mechanism underlying the pathogenesis of CRC remains to be elucidated. Studies that explore the molecular mechanisms contributing to the growth of CRC cells are urgently needed in order to develop novel therapeutic strategies. Intracellular calcium (Ca2+), which is a ubiquitous second messenger, plays important roles in various types of biological events. Owing to the significance of Ca2+ in signaling pathways, the level of Ca2+ in cells is strictly controlled.

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