BNIP3 in Cyanide-induced Brain Damage

In this study, an immortalized dopaminergic cell line was used to characterize the cell death signaling cascade activated by cyanide. Cyanide activated the HIF-1α-mediated pathway of BNIP3 induction through a redox-sensitive process. Increased BNIP3 expression then served as an initiator of mitochondria-mediated death. In mice, repeated exposure to a sublethal dose of cyanide resulted in an increase of BNIP3 expression in midbrain, which was accompanied by a loss of dopaminergic neurons. In cortex, cyanide induced upregulation of BNIP3, which may be involved in cortical cell apoptosis. It is also shown that BNIP3 was localized in both ER and mitochondria to facilitate the release of Ca2+ from ER and subsequently increase uptake of Ca2+ into mitochondria. Excessive accumulation of mitochondrial Ca2+ facilitated the loss of ΔΨm, ultimately resulting in the execution of cell death. Current results also confirm that Bax was activated and co-localized with BNIP3 in ER and mitochondria. Acting as a downstream effector for BNIP3, Bax is required for Ca2+ crosstalk between ER and mitochondria, thereby contributing to mitochondria-mediated cell apoptosis.