The Effects And Mechanisms Of Mitochondrial Transcription Factor A On Tumor Radiation Sensitivity

Mitochondrial transcription factor A(TFAM)is a member of the HMG protein family.It is known to regulate mitochondrial DNA(mtDNA)copy number and transcriptional activity,apoptosis,and act as a mitochondrial damage-associated molecular patterns(DAMPs)into the cellular microenvironment.This study focused on the effects of TFAM on tumor radiation sensitivity and its role in tumor microenvironment.Part Ⅰ:The effect of TFAM on tumor radiation sensitivity and related mechanisms Mitochondria are important targets for ionizing radiation and are more susceptible to ionizing radiation due to the special structure and function.As an important transcriptional and regulatory factor of mitochondrial DNA,TFAM binds to mitochondrial DNA and regulates mitochondrial biogenesis.Our research centered on TFAM-mediated mitochondrial biogenesis and revealed the underlying mechanisms of mitochondrial biogenesis response to ionizing radiation.Our study found that ionizing radiation stimulated the expression of TFAM.To further explore the effects of TFAM on tumor radiation sensitivity,we constructed a stable cell line with TFAM knockout.Studies have shown that the loss of TFAM results in the decrease of mitochondrial copy number,cell proliferation,clony formation,and the increase of apoptosis,suggesting that TFAM knockdown increases tumor radiation sensitivity.We further explored the mechanism.Studies have found that ionizing radiation can promote the binding of RNA-binding protein HuR to TFAM mRNA,thereby increasing the stability of TFAM mRNA.Furthermore,radiation-activated ataxia-telangiectasia mutated kinase/p38 signaling positively contributed to the nucleus to cytosol translocation of HuR,its binding and stabilization of TFAM mRNA.Our work proposed a new mechanism of DNA damage response-regulated mitochondrial function variations,and indicated that TFAM might be a potential target for increasing the sensitization of cancer cells to radiotherapy.Part Ⅱ:DJ-1 induces TFAM secretion and related mechanismsOur research found that y-rays can not only induce the increase of TFAM expression in tumor cells,but induce the secretion of TFAM.The release of TFAM inhibit ionizing radiation-induced DNA damage and reduce tumor radiation sensitivity.To further investigate the effects of oxidative stress on TFAM release,we explored the whether protein DJ-1 which is closely related to cellular oxidative stress regulates TFAM release.As an antioxidant protein.Studies have found that deletion of DJ-1 induces TFAM release and inhibits DJ-1 knockdown-induced apoptosis.Further studies have found that DJ-1 deletion can induce p53-mediated non-transcription-dependent apoptosis,which promotes the secretion of TFAM.In addition,knockdown of DJ-1 inhibits the expression of deacetylase SIRT3,which decreases TFAM acetylation modification.These results preliminarily demonstrates that p53-induced apoptosis and TFAM acetylation modification are closely related to the secretion of TFAM.Our study reveals that in the induction of ionizing radiation,intracellular expression and extracellular secretion of TFAM play a key role in inhibiting apoptosis and promoting cell proliferation,whereas deletion or neutralization of TFAM significantly increases tumor radiation sensitivity.This study provides a theoretical basis for further understanding the regulation mechanism of mitochondria on tumor cell response and the establishment of mitochondria-targeted tumor radiotherapy strategy.