NIX is required for programmed mitochondrial clearance during reticulocyte maturation

doi:10.1073/pnas.0708818104

NIX is required for programmed mitochondrial clearance during reticulocyte maturation

*Department of Biochemistry, St. Jude Children's Research Hospital, Memphis, TN 38105;
^†Integrated Program in Biomedical Sciences, University of Tennessee Health Science Center, Memphis, TN 38126;
^‡Department of Cancer Biology, The Scripps Research Institute-Florida, Jupiter, FL 33458;
^§Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104; and
^¶Molecular Medicine Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892

Edited by Stuart H. Orkin, Harvard Medical School, Boston, MA, and approved October 17, 2007 (received for review September 17, 2007)

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.

Footnotes

^‖To whom correspondence should be addressed at:
Department of Biochemistry, St. Jude Children's Research Hospital, 332 North Lauderdale Street, Memphis, TN 38105-2794.
E-mail: paul.ney{at}stjude.org
Author contributions: R.L.S., J.Z., M.S.R., and M.R.L. contributed equally to this work; R.L.S., J.Z., F.C.D., M.K., J.T.O., J.L.M., and P.A.N. designed research; R.L.S., J.Z., M.S.R., M.R.L., W.L., and F.C.D. performed research; and J.L.C. and P.A.N. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0708818104/DC1.