BNIP3 is a pro-apoptotic, mitochondrial protein classified in the Bcl 2 family. BNIP3 expressed in yeast and mammalian cells interacts with survival promoting proteins Bcl 2, Bcl XL, CED9 and the adenovirus E1B 19K protein. BNIP3 represents a subfamily of Bcl 2 related proteins, which function without a typical BH3 domain to regulate apoptosis from both mitochondrial and nonmitochondrial sites by selective Bcl 2/Bcl XL interactions. The N-terminus (aa1-49) and the C-terminus TM domain of BNIP3 are critical for Bcl 2 hetero- dimerization, and either region is sufficient for Bcl XL interaction. The TM domain of BNIP3 is critical for homodimerization, pro-apoptotic function and mitochondrial targeting. BNIP3 contains PEST sequences suggesting that the protein may be susceptible to rapid degradation by proteases. The post- translational control of BNIP3 expression through rapid protein degradation may constitute a mechanism for regulating the intracellular levels of a potentially lethal protein. Homologues of BNIP3 sharing both structural and functional similarity have been identified in mammals (Nix) and, in C. elegans (ceBNIP3). Endogenous BNIP3 is loosely associated with mitochondrial membrane in normal tissue but fully integrates into the mitochondrial outer membrane with the N-terminus in the cytoplasm and the C-terminus in the membrane during induction of cell death. This is accompanied by rapid and profound mitochondrial dysfunction. Endogenous BNIP3 protein is abundant in murine andhuman skeletal muscle and is not detectable in lysates of all other nonskeletal muscle-bearing tissues and many cell lines, including myoblasts and differentiated myocytes.