Mitochondrial protein COXFA4L3 (C15ORF48) confers resistance to DNA-damaging anticancer agents by repressing mitochondrial DNA damage responses.

DNA-damaging anticancer agents selectively kill highly proliferative cancer cells by inducing DNA damage, such as DNA double- or single-strand breaks, and by inhibiting DNA replication and transcription. These agents have been used for cancer chemotherapy for a long time; however, acquired resistance remains a serious problem that limits their effectiveness. Although mitochondria have their own DNA, which is distinct from nuclear DNA, the involvement of mitochondria and mitochondrial DNA (mtDNA) in resistance to DNA-damaging anticancer agents remains largely unknown. In this study, we found that the mitochondrial small protein cytochrome c oxidase-associated subunit FA4-like 3 (COXFA4L3), formerly known as C15ORF48, confers resistance to DNA-damaging anticancer agents. Mechanistically, DNA-damaging anticancer agents damage mtDNA and induce the cytosolic release of TFAM-unbound mtDNA via the mitochondrial permeability transition pore (mPTP), thereby promoting cell death via activation of the innate immune signalling cGAS-STING pathway. COXFA4L3 inhibits the cytosolic release of mtDNA by repressing mtDNA damage and mPTP opening. These results suggest that mitochondria affect sensitivity to DNA-damaging anticancer agents through COXFA4L3-mediated repression of mtDNA damage responses.