Radiation resistance of cancer cells caused by mitochondrial dysfunction depends on SIRT3-mediated mitophagy.

Radiation resistance is the leading cause of radiotherapy failure in patients with cancer. Enhanced DNA damage repair is the main reason for cancer cells to develop resistance to radiation. Autophagy has been widely reported to be linked to increased genome stability and radiation resistance. Mitochondria are highly involved in cell response to radiotherapy. However, the autophagy subtype mitophagy has not been studied in terms of genome stability. We have previously demonstrated that mitochondrial dysfunction is the cause of radiation resistance in tumor cells. We found in this study that SIRT3 was highly expressed in colorectal cancer cells with mitochondrial dysfunction, leading to PINK1/Parkin-mediated mitophagy. Excessive activation of mitophagy enhanced DNA damage repair, therefore promoting the resistance of tumor cells to radiation. Mechanistically, mitophagy resulted in decreased RING1b expression, which led to a reduction in the ubiquitination of histone H2A at K119, thereby enhancing the repair of DNA damage caused by radiation. Additionally, high expression of SIRT3 was related to a poor tumor regression grade in rectal cancer patients treated with neoadjuvant radiotherapy. These findings suggest that restoring mitochondrial function could be an effective method for increasing the radiosensitivity of patients with colorectal cancer.