BNIP/NIX promotes mitophagy through direct interaction with LC3 at the phagophore. BNIP3 and NIX are both hypoxia-inducible genes that encode molecular adaptors that promote mitophagy through interaction with processed LC3-related molecules at nascent phagophores (A). Both BNIP3 and NIX interact with Bcl-2 and Bcl-XL through their amino terminal ends, and Bcl-2/Bcl-XL has been postulated to play both positive and negative regulatory effects on BNIP3 function (A). BNip3 has also been shown to interact with regulators of mitochondrial fission (Drp-1) and mitochondrial fusion (Opa-1). These interactions are positive and negative, respectively, resulting in a role for BNIP3 in promoting fission while inhibiting fusion (B). BNIP3 has also been shown to interact with the small GTPase, Rheb, resulting in reduced Rheb activity, reduced mTOR activity, and reduced cell growth (C). This function for BNIP3 in modulating Rheb (C) contrasts with the proposed functional interaction of NIX with Rheb (D) that elicits a mTOR-independent effect on mitophagy by promoting LC3 processing and increased mitochondrial turnover in cells grown on oxidative substrates (D). NIX is required for recruitment of Rheb to mitochondria and its activating effect on mitophagy.