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PMID: 18048346 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

NIX is required for programmed mitochondrial clearance during reticulocyte maturation.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 104 ·No. 49 ·2007-12-04 ·Pages 19500-5

Schweers RL, Zhang J, Randall MS, Loyd MR, Li W, Dorsey FC, Kundu M, Opferman JT, Cleveland JL, Miller JL, Ney PA

Abstract

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.

MeSH Terms
Animals Apoptosis/genetics Autophagy/genetics Erythropoiesis/genetics Humans Membrane Proteins/genetics,physiology Mice Mice, Transgenic Mitochondria/metabolism Proto-Oncogene Proteins/genetics,physiology Proto-Oncogene Proteins c-bcl-2/genetics,metabolism Reticulocytes/metabolism,physiology,ultrastructure Tumor Suppressor Proteins/genetics,physiology Ubiquitin/metabolism
Chemicals
BNIP3L protein, human Membrane Proteins Proto-Oncogene Proteins Proto-Oncogene Proteins c-bcl-2 Tumor Suppressor Proteins Ubiquitin
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Schweers Rachel L
Department of Biochemistry, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Zhang Ji
Randall Mindy S
Loyd Melanie R
Li Weimin
Dorsey Frank C
Kundu Mondira
Opferman Joseph T
Cleveland John L
Miller Jeffery L
Ney Paul A
References (44)
44 references, click to expand
  1. LC3, GABARAP and GATE16 localize to autophagosomal membrane depending on form-II formation.
    J Cell Sci. 2004 Jun 1;117(Pt 13):2805-12 PMID: 15169837
  2. Unrestrained erythroblast development in Nix-/- mice reveals a mechanism for apoptotic modulation of erythropoiesis.
    Proc Natl Acad Sci U S A. 2007 Apr 17;104(16):6794-9 PMID: 17420462
  3. Isolation, mapping, and functional analysis of a novel human cDNA (BNIP3L) encoding a protein homologous to human NIP3.
    Genes Chromosomes Cancer. 1998 Mar;21(3):230-5 PMID: 9523198
  4. Splenic erythroblasts in anemia-inducing Friend disease: a source of cells for studies of erythropoietin-mediated differentiation.
    J Cell Physiol. 1984 Dec;121(3):526-32 PMID: 6501430
  5. Cre-mediated gene deletion in the mammary gland.
    Nucleic Acids Res. 1997 Nov 1;25(21):4323-30 PMID: 9336464
  6. Platelet formation is the consequence of caspase activation within megakaryocytes.
    Blood. 2002 Aug 15;100(4):1310-7 PMID: 12149212
  7. Selective and non-selective autophagic degradation of mitochondria in yeast.
    Autophagy. 2007 Jul-Aug;3(4):329-36 PMID: 17377488
  8. Cell death: critical control points.
    Cell. 2004 Jan 23;116(2):205-19 PMID: 14744432
  9. Aup1p, a yeast mitochondrial protein phosphatase homolog, is required for efficient stationary phase mitophagy and cell survival.
    J Biol Chem. 2007 Feb 23;282(8):5617-24 PMID: 17166847
  10. Nix and Nip3 form a subfamily of pro-apoptotic mitochondrial proteins.
    J Biol Chem. 1999 Jan 1;274(1):7-10 PMID: 9867803
  11. Mitochondrial death protein Nix is induced in cardiac hypertrophy and triggers apoptotic cardiomyopathy.
    Nat Med. 2002 Jul;8(7):725-30 PMID: 12053174
  12. Organelle degradation during the lens and erythroid differentiation is independent of autophagy.
    Biochem Biophys Res Commun. 2006 Jan 13;339(2):485-9 PMID: 16300732
  13. Essential role of BAX,BAK in B cell homeostasis and prevention of autoimmune disease.
    Proc Natl Acad Sci U S A. 2005 Aug 9;102(32):11272-7 PMID: 16055554
  14. Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice.
    J Cell Biol. 2005 May 9;169(3):425-34 PMID: 15866887
  15. Reticulocyte counting using flow cytometry.
    J Clin Pathol. 1990 Aug;43(8):675-8 PMID: 2401736
  16. Proapoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death.
    Science. 2001 Apr 27;292(5517):727-30 PMID: 11326099
  17. Distinct BH3 domains either sensitize or activate mitochondrial apoptosis, serving as prototype cancer therapeutics.
    Cancer Cell. 2002 Sep;2(3):183-92 PMID: 12242151
  18. HIF-1-dependent regulation of hypoxic induction of the cell death factors BNIP3 and NIX in human tumors.
    Cancer Res. 2001 Sep 15;61(18):6669-73 PMID: 11559532
  19. Adenovirus E1B 19 kDa and Bcl-2 proteins interact with a common set of cellular proteins.
    Cell. 1994 Oct 21;79(2):341-51 PMID: 7954800
  20. Adenovirus E1B-19K/BCL-2 interacting protein BNIP3 contains a BH3 domain and a mitochondrial targeting sequence.
    J Biol Chem. 1998 May 15;273(20):12415-21 PMID: 9575197
  21. Autophagy: molecular machinery for self-eating.
    Cell Death Differ. 2005 Nov;12 Suppl 2:1542-52 PMID: 16247502
  22. Bnip3L is induced by p53 under hypoxia, and its knockdown promotes tumor growth.
    Cancer Cell. 2004 Dec;6(6):597-609 PMID: 15607964
  23. Functional and physical interaction between Bcl-X(L) and a BH3-like domain in Beclin-1.
    EMBO J. 2007 May 16;26(10):2527-39 PMID: 17446862
  24. Bcl-2 prolongs cell survival after Bax-induced release of cytochrome c.
    Nature. 1998 Jan 29;391(6666):496-9 PMID: 9461218
  25. Bcl-2/E1B 19 kDa-interacting protein 3-like protein (Bnip3L) interacts with bcl-2/Bcl-xL and induces apoptosis by altering mitochondrial membrane permeability.
    Oncogene. 1999 Aug 12;18(32):4523-9 PMID: 10467396
  26. The E1B 19K/Bcl-2-binding protein Nip3 is a dimeric mitochondrial protein that activates apoptosis.
    J Exp Med. 1997 Dec 15;186(12):1975-83 PMID: 9396766
  27. Apoptosis initiated when BH3 ligands engage multiple Bcl-2 homologs, not Bax or Bak.
    Science. 2007 Feb 9;315(5813):856-9 PMID: 17289999
  28. Caspase activity and a specific cytochrome C are required for sperm differentiation in Drosophila.
    Dev Cell. 2003 May;4(5):687-97 PMID: 12737804
  29. Hierarchical regulation of mitochondrion-dependent apoptosis by BCL-2 subfamilies.
    Nat Cell Biol. 2006 Dec;8(12):1348-58 PMID: 17115033
  30. Mitochondria primed by death signals determine cellular addiction to antiapoptotic BCL-2 family members.
    Cancer Cell. 2006 May;9(5):351-65 PMID: 16697956
  31. A function for lipoxygenase in programmed organelle degradation.
    Nature. 1998 Sep 24;395(6700):392-5 PMID: 9759730
  32. The combined functions of proapoptotic Bcl-2 family members bak and bax are essential for normal development of multiple tissues.
    Mol Cell. 2000 Dec;6(6):1389-99 PMID: 11163212
  33. BNIP3 is an RB/E2F target gene required for hypoxia-induced autophagy.
    Mol Cell Biol. 2007 Sep;27(17):6229-42 PMID: 17576813
  34. Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy.
    Cell. 2005 Sep 23;122(6):927-39 PMID: 16179260
  35. Autophagic and tumour suppressor activity of a novel Beclin1-binding protein UVRAG.
    Nat Cell Biol. 2006 Jul;8(7):688-99 PMID: 16799551
  36. Bcl-x(L) prevents apoptosis of late-stage erythroblasts but does not mediate the antiapoptotic effect of erythropoietin.
    Blood. 2005 Sep 1;106(5):1857-63 PMID: 15899920
  37. Conditional deletion of the Bcl-x gene from erythroid cells results in hemolytic anemia and profound splenomegaly.
    Development. 2000 Nov;127(22):4949-58 PMID: 11044408
  38. Bax directly induces release of cytochrome c from isolated mitochondria.
    Proc Natl Acad Sci U S A. 1998 Apr 28;95(9):4997-5002 PMID: 9560217
  39. Distinct pathways regulate proapoptotic Nix and BNip3 in cardiac stress.
    J Biol Chem. 2006 Jan 20;281(3):1442-8 PMID: 16291751
  40. BNIP3 and genetic control of necrosis-like cell death through the mitochondrial permeability transition pore.
    Mol Cell Biol. 2000 Aug;20(15):5454-68 PMID: 10891486
  41. Expression of the gene encoding the proapoptotic Nip3 protein is induced by hypoxia.
    Proc Natl Acad Sci U S A. 2000 Aug 1;97(16):9082-7 PMID: 10922063
  42. LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing.
    EMBO J. 2000 Nov 1;19(21):5720-8 PMID: 11060023
  43. The proapoptotic factor Nix is coexpressed with Bcl-xL during terminal erythroid differentiation.
    Blood. 2003 Jul 15;102(2):712-7 PMID: 12663450
  44. Puma is an essential mediator of p53-dependent and -independent apoptotic pathways.
    Cancer Cell. 2003 Oct;4(4):321-8 PMID: 14585359
Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
1091-6490
DOI
10.1073/pnas.0708818104
Published
2007-12-04
Epub
2007-00-29
Pages
19500-5
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC2148318
Subset
IM
Grants
NCI NIH HHS · R01 CA084214-08 · United States
NCI NIH HHS · R01 CA084214-07 · United States
NCI NIH HHS · R01 CA084214-06A1 · United States
NIDDK NIH HHS · R21 DK074519 · United States
NCI NIH HHS · R01 CA084214 · United States
NIDDK NIH HHS · R21 DK074519-02 · United States
NCI NIH HHS · R01 CA084214-09 · United States
NIDDK NIH HHS · R21 DK074519-01 · United States
NCI NIH HHS · R01 CA084214-10 · United States
External Links
PubMed source DOI: 10.1073/pnas.0708818104 PMC Full Text View journal details
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