摘要
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 MCUmediated 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 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 Ca^(2+)uptake promotes mitochondrial biogenesis by suppressing phosphorylation of TFAM,thus contributing to CRC cell growth.Our findings reveal a novel mechanism underlying mitochondrial Ca^(2+)-mediated CRC cell growth and may provide a potential pharmacological target for CRC treatment.
基金
supported by the National Natural Science Foundation of China(grants 81872302 and 81902513)
Science and Technology Co-ordinate Innovation Project of Shaanxi Province,China(grants 2016TZC-S-18-1).
