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

作者：Liu Yang, Mingpeng Jin, Yaya Wang, Jianjun Zhu, Rui Tan, Jing Zhao, Xiaoying Ji, Chao Jin, Yongfeng Jia, Tingting Ren, Jinliang Xing · 发表于：Signal Transduction and Targeted Therapy · 年份：2020 · DOI：10.1038/s41392-020-0155-5 · 被引用次数：152 · 研究领域：Mitochondrial Function and Pathology、ATP Synthase and ATPases Research、Bone Metabolism and Diseases

Abstract Mitochondrial calcium uniporter (MCU) has an important role in regulating mitochondrial calcium (Ca 2+ ) homeostasis. Dysregulation of mitochondrial Ca 2+ homeostasis has been implicated in various cancers. However, it remains unclear whether MCU regulates mitochondrial Ca 2+ 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 Ca 2+ 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 Ca 2+ 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 Ca 2+ 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 Ca 2+ uptake led to increased mitochondrial production...