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

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.

• Authors: Yang Liu, Mingpeng Jin, Yaya Wang, Jianjun Zhu, Rui Tan, Jing Zhao, Xiaoying Ji, Chao Jin, Yongfeng Jia, Tingting Ren, Jinliang Xing
• Journal: Signal transduction and targeted therapy (Signal Transduct Target Ther) Vol. 5 Issue 1 Pg. 59 (05 05 2020) ISSN: 2059-3635 [Electronic] England
• PMID: 32371956 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Calcium Channels
• Mitochondrial Proteins
• Neoplasm Proteins
• mitochondrial calcium uniporter

Topics

• Animals
• Caco-2 Cells
• Calcium Channels (genetics, metabolism)
• Colorectal Neoplasms (genetics, metabolism, pathology)
• HT29 Cells
• Humans
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Mitochondria (genetics, metabolism, pathology)
• Mitochondrial Proteins (genetics, metabolism)
• Neoplasm Proteins (genetics, metabolism)
• Organelle Biogenesis