TY - JOUR T1 - Cyanide-Induced Apoptosis of Dopaminergic Cells Is Promoted by BNIP3 and Bax Modulation of Endoplasmic Reticulum-Mitochondrial Ca<sup>2+</sup> Levels JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 97 LP - 105 DO - 10.1124/jpet.109.159103 VL - 332 IS - 1 AU - Lu Zhang AU - Li Li AU - Heather W. Leavesley AU - Xun Zhang AU - Joseph L. Borowitz AU - Gary E. Isom Y1 - 2010/01/01 UR - http://jpet.aspetjournals.org/content/332/1/97.abstract N2 - Cyanide is a potent neurotoxicant that can produce dopaminergic neuronal death in the substantia nigra and is associated with a Parkinson-like syndrome. In this study involvement of Bcl-2/adenovirus E1B 19-kDa interacting protein 3 (BNIP3), a BH3-only Bcl-2 protein, in cyanide-induced death of dopaminergic cells was determined in mice and Mes 23.5 cells. Treatment of mice with cyanide up-regulated BNIP3 and Bax expression in tyrosine hydroxylase (TH)-positive cells of the substantia nigra, and progressive loss of TH-positive neurons was observed over a 9-day period. In Mes 23.5 dopaminergic cells, cyanide stimulated translocalization of BNIP3 to both endoplasmic reticulum (ER) and mitochondria. In ER, BNIP3 stimulated release of Ca2+ into the cytosol, followed by accumulation of mitochondrial Ca2+, resulting in reduction of mitochondrial membrane potential (Δψm) and eventually cell death. Cyanide also activated Bax to colocalize with BNIP3 in ER and mitochondria. Forced overexpression of BNIP3 activated Bax, whereas gene silencing reduced Bax activity. Knockdown of Bax expression by small interfering RNA blocked the BNIP3-mediated changes in ER and mitochondrial Ca2+ to block cyanide-induced mitochondrial dysfunction and cell death. These findings show that BNIP3-mediates cyanide-induced dopaminergic cell death through a Bax downstream signal that mobilizes ER Ca2+ stores, followed by mitochondrial Ca2+ overload.© 2010 by The American Society for Pharmacology and Experimental Therapeutics ER -