ABCB7 simultaneously regulates apoptotic and non-apoptotic cell death by modulating mitochondrial ROS and HIF1α-driven NFκB signaling.

Most of the mechanisms governing apoptotic and non-apoptotic cell death are regulated independently. However, cells may experience various stresses that lead to both apoptotic and non-apoptotic cell death. In particular, cancer cells require a program that simultaneously avoids these forms of cell death, but the mechanism by which they are able to do so is currently unclear. Here, we show that ABC transporter subfamily B member 7 (ABCB7), one of the mitochondrial iron transporters, induces the hypoxia-independent accumulation of hypoxia-inducible factor 1 alpha by controlling intracellular iron homeostasis and inhibits both apoptotic and non-apoptotic cell death. Mechanistically, ABCB7 mitigates non-apoptotic cell death by reducing levels of mitochondrial reactive oxygen species. ABCB7 also suppresses apoptosis by inhibiting the expression of leucine zipper downregulated in cancer 1, an inhibitor of nuclear factor-kappa B signaling. Therefore, our results support that ABCB7 is crucial in controlling both apoptotic and non-apoptotic cell death and indicate that the fine-tuning of intracellular iron homeostasis may be a novel anticancer strategy.