NIX is required for programmed mitochondrial clearance during reticulocyte maturation.
The regulated clearance of mitochondria is a well recognized but poorly understood aspect of cellular homeostasis, and defects in this process have been linked to aging, degenerative diseases, and cancer. Mitochondria are recycled through an autophagy-related process, and reticulocytes, which completely eliminate their mitochondria during maturation, provide a physiological model to study this phenomenon. Here, we show that mitochondrial clearance in reticulocytes requires the BCL2-related protein NIX (BNIP3L). Mitochondrial clearance does not require BAX, BAK, BCL-X(L), BIM, or PUMA, indicating that NIX does not function through established proapoptotic pathways. Similarly, NIX is not required for the induction of autophagy during terminal erythroid differentiation. NIX is required for the selective elimination of mitochondria, however, because mitochondrial clearance, in the absence of NIX, is arrested at the stage of mitochondrial incorporation into autophagosomes and autophagosome maturation. These results yield insight into the mechanism of mitochondrial clearance in higher eukaryotes. Furthermore, they show a BAX- and BAK-independent role for a BCL2-related protein in development.
Department of Biochemistry, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Rachel L
RL
Schweers
Ji
J
Zhang
Mindy S
MS
Randall
Melanie R
MR
Loyd
Weimin
W
Li
Frank C
FC
Dorsey
Mondira
M
Kundu
Joseph T
JT
Opferman
John L
JL
Cleveland
Jeffery L
JL
Miller
Paul A
PA
Ney
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001343:Autophagy / Q000235:genetics; D004920:Erythropoiesis / Q000235:genetics; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D012156:Reticulocytes / Q000378:metabolism / Q000502:physiology* / Q000648:ultrastructure; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000502:physiology*; D025801:Ubiquitin / Q000378:metabolism
C116838:BNIP3L protein, human; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D025521:Tumor Suppressor Proteins; D025801:Ubiquitin