Transcriptionally induced NIX is targeted to the mitochondria and ER/SR and activates programmed cell death in cells via a canonical mitochondrial pathway and what we believe is a novel ER/SR pathway. Mitochondria-targeted Nix causes mitochondrial outer membrane permeabilization, likely in coordination with Bax and Bak, leading to cytochrome c release, apoptosome formation, caspase 3 activation and apoptotic cell death. ER/SR-targeted Nix contributes to ER/SR calcium overload. This sensitizes cells to environmental stimuli, resulting in local calcium release at junctional “hot spots” with mitochondria. Released calcium is taken up by a mitochondrial uniporter, causing intramitochondrial calcium overload that triggers mitochondrial permeability pore formation with loss of mitochondrial potential, mitochondrial swelling, and release of essential mitochondrial proteins, preventing ATP generation with resultant bioenergetic failure. This is rapidly followed by failure of energy-dependent, plasma membrane–localized ion transporters, causing intracellular ion overload, cellular swelling and rupture, and necrotic cell death. MPTP, mitochondrial permeability transition pore.