Mitochondrial Dysfunction Induces Radioresistance In Colorectal Cancer By Activating [Ca²⁺]_m-PDP1-PDH-Histone Acetylation Retrograde Signaling

Purpose Radiotherapy is one of the most important treatments for colorectal cancer cells(CRC)patients.However,intrinsic radioresistance of CRC cells usually leads to recurrence or metastasis in patients who received radiotherapy and results in poor prognosis.Our previous studies showed mitochondrial dysfunction contributed to intrinsic radioresistance and glycolysis.And phos-pyruvate dehydrogenase(p-PDH),which involved in aerobic glycolysis,was positively correlated with radioresistance,but how it initiate and work in the mitochondrial retrograde signaling pathway is still unknown.Methods We performed genomics analysis to identify differential mitochondrial complex ? genes in radioresistant cells that we constructed perviously.Then,we downregulated complex ? activity with rotenone to evaluate the effect of complex I function on radiosensitivity.To study the mechanism of radioresistance,the levels of mitochondrial membrane potential,[Ca2+]m/PDP1,cytoplasmic and nuclear PDH expression as well as histone acetylation were determined,in colorectal cancer cells treated with rotenone and in complex ? deficient cells that elevated complex ? activity by overexpressing NDUFS1(complex ? component).Meanwhile,overexpressing NDUFS1 in vivo and in vitro to improve the oxidative respiration capacity of mitochondria,and then detected the sensitivity of tumor cells to radiation.Finally,the relationship between NDUFS1,PDH and tumor regression grading(TRG)were explored in clinical pathological tissues treated with neoadjuvant radiotherapy.Results Downregulated complex ? components were found to be related to radioresistance in the results of genomics analysis and public database.Complex ?deficient cells exhibited enhanced DNA damage repair and high p-PDH expression.Mechanistically,complex ? defects lead to decreased PDH both in cytoplasm and nucleus through[Ca2+]m-PDP1-PDH axis,and decreased PDH in nucleus promote DNA damage repair response via reducing histone acetylation.Meanwhile,overexpression of NDUFS1 can reverse glycolysis and resensitize cancer cells to radiation in vivo and in vitro.Furthermore,low NDUFS1 and PDH expression were validated to be correlated with poor TRG in local advanced CRC patients underwent neoadjuvant radiotherapy.Conclusion Here,we propose that the[Ca2+]m-PDP1-PDH-histone acetylation retrograde signaling activated by complex ? defects contribute to cancer cell radioresistance and modification of complex ? function may improve clinical benefits of radiotherapy in CRC.