Essential role for Nix in autophagic maturation of erythroid cells.
Erythroid cells undergo enucleation and the removal of organelles during terminal differentiation. Although autophagy has been suggested to mediate the elimination of organelles for erythroid maturation, the molecular mechanisms underlying this process remain undefined. Here we report a role for a Bcl-2 family member, Nix (also called Bnip3L), 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 (DeltaPsi(m)), and treatment with uncoupling chemicals or a BH3 mimetic induced the loss of DeltaPsi(m) and restored the sequestration of mitochondria into autophagosomes in Nix(-/-) erythroid cells. These results suggest that Nix-dependent loss of DeltaPsi(m) 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.
Sandoval
Hector
H
Department of Immunology, Baylor College of Medicine, Houston, Texas 77030, USA.
Thiagarajan
Perumal
P
Dasgupta
Swapan K
SK
Schumacher
Armin
A
Prchal
Josef T
JT
Chen
Min
M
Wang
Jin
J
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D001713:Biphenyl Compounds / Q000494:pharmacology; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D053595:Embryonic Stem Cells / Q000166:cytology / Q000187:drug effects; D041905:Erythroid Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D004920:Erythropoiesis / Q000187:drug effects; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D024101:Mitochondrial Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D009596:Nitrophenols / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D012156:Reticulocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology
C501332:ABT-737; D001713:Biphenyl Compounds; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D009596:Nitrophenols; C501741:Nix protein, mouse; D010879:Piperazines; D013449:Sulfonamides; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone