NIX induces mitochondrial autophagy in reticulocytes.
The controlled elimination of defective mitochondria is necessary for the health of long-lived post-mitotic cells, like cardiomyocytes and neurons. Mitochondrial elimination also occurs during the course of normal development, in lens epithelial and erythroid cells. Strikingly, at the final stage of erythroid cell maturation, newly formed erythrocytes, also known as reticulocytes, eliminate their entire cohort of mitochondria. We have employed this model to investigate the mechanism of programmed mitochondrial clearance. NIX (BNIP3L) is a Bcl-2-related protein that is upregulated during terminal erythroid differentiation. NIX-deficient reticulocytes have a significant defect of mitochondrial clearance. Consistent with the ability of NIX to cause mitochondrial depolarization, we show that mitochondria are depolarized in wild type but not NIX deficient reticulocytes. NIX does not function through established proapoptotic pathways, nor does it mediate the induction of autophagy in erythroid cells. Rather, NIX is required for the selective incorporation of mitochondria into autophagosomes. Elucidation of the mechanism of this effect will improve our understanding of the role of autophagy in the maintenance of cellular homeostasis.
Zhang
Ji
J
Department of Biochemistry, St. Jude Children's Hospital, Memphis, Tennessee USA. paul.ney@stjude.org
Ney
Paul A
PA
D000818:Animals; D001343:Autophagy / Q000502:physiology*; D002454:Cell Differentiation; D004920:Erythropoiesis; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000502:physiology*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000502:physiology*; D010588:Phagosomes / Q000502:physiology; D012156:Reticulocytes / Q000502:physiology* / Q000648:ultrastructure; D054875:Ubiquitination; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000502:physiology; D051028:bcl-2-Associated X Protein / Q000502:physiology
C494773:Bak1 protein, mouse; C494827:Bax protein, mouse; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; C501741:Nix protein, mouse; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein