Essential role for Nix in autophagic maturation of erythroid cells

Abstract

Erythroid cells undergo enucleation and the removal of organelles during terminal differentiation. This paper shows that a member of the Bcl-2 family, Nix/Bnip3L, helps eliminate organelles by by autophagy (or 'eating') of the mitochondria. Nix−/− mice developed anaemia with reduced mature erythrocytes and compensatory expansion of erythroid precursors. Erythrocytes in the peripheral blood of Nix−/− mice exhibited mitochondrial retention and reduced lifespan in vivo. This work may shed light on the mechanisms for various anaemic conditions associated with defective autophagy. It may also help to understand the molecular regulation of autophagy under normal and disease settings in other cell types. This paper shows that a member of the Bcl-2 family, Nix, helps eliminate organelles by autophagy of the mitochondria. Erythrocytes in the peripheral blood of Nix−/− mice exhibited mitochondrial retention and reduced lifespan in vivo. Erythroid cells undergo enucleation and the removal of organelles during terminal differentiation1,2,3. Although autophagy has been suggested to mediate the elimination of organelles for erythroid maturation2,3,4,5,6, the molecular mechanisms underlying this process remain undefined. Here we report a role for a Bcl-2 family member, Nix (also called Bnip3L)7,8,9, in the regulation of erythroid maturation through mitochondrial autophagy. Nix-/- mice developed anaemia with reduced mature erythrocytes and compensatory expansion of erythroid precursors. Erythrocytes in the peripheral blood of Nix-/- mice exhibited mitochondrial retention and reduced lifespan in vivo. Although the clearance of ribosomes proceeded normally in the absence of Nix, the entry of mitochondria into autophagosomes for clearance was defective. Deficiency in Nix inhibited the loss of mitochondrial membrane potential (ΔΨm), and treatment with uncoupling chemicals or a BH3 mimetic induced the loss of ΔΨm and restored the sequestration of mitochondria into autophagosomes in Nix-/- erythroid cells. These results suggest that Nix-dependent loss of ΔΨm is important for targeting the mitochondria into autophagosomes for clearance during erythroid maturation, and interference with this function impairs erythroid maturation and results in anaemia. Our study may also provide insights into molecular mechanisms underlying mitochondrial quality control involving mitochondrial autophagy.