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Mitochondrial clearance by autophagy in developing erythrocytes: Clearly important, but just how much so?

Nuffield Department of Medicine, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, UK.
Cell cycle (Georgetown, Tex.) (Impact Factor: 5.01). 05/2010; 9(10):1901-6. DOI: 10.4161/cc.9.10.11603
Source: PubMed

ABSTRACT Erythrocytes are anucleated cells devoid of organelles. Expulsion of the nucleus from erythroblasts leads to the formation of reticulocytes, which still contain organelles. The mechanisms responsible for the final removal of organelles from developing erythroid cells are still being elucidated. Mitochondria are the most abundant organelles to be cleared for the completion of erythropoiesis. Macroautophagy, referred to as autophagy, is a regulated catabolic pathway consisting of the engulfment of cytoplasmic cargo by a double membraned-vesicle, the autophagosome, which typically then fuses to lysosomal compartments for the degradation of the sequestered material. Early electron microscopic observations of reticulocytes suggested the autophagic engulfment of mitochondria (mitophagy) as a possible mechanism for mitochondrial clearance in these. Recently, a number of studies have backed this hypothesis with molecular evidence. Indeed, the absence of Nix, which targets mitochondria to autophagosomes, or the deficiency of proteins in the autophagic pathway lead to impaired mitochondrial clearance from developing erythroid cells. Importantly, however, the extent to which the absence of mitophagy affects erythroid development differs depending on the model and gene investigated. This review will therefore focus on comparing the different studies of mitophagy in erythroid development and highlight some of the remaining controversial points.

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    • "In addition to intracellular degradation initiated by ALOX15 [70], there are two competing hypotheses for how mitochondrial degradation occurs in erythroid cells [79]: i) engulfment and digestion within autophagic vacuoles [80]; and ii) exocytosis of mitochondria within exosomes [81]. There is experimental support for all three scenarios, but none of the proposed mechanisms appears to provide a complete answer [82]. It may simply be that inhibition of one pathway can be compensated for by one or both of the others. "
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    • "Nix was recently found to bind the mammalian LC3 and GABARAP and thus recruit forming autophagosomes to depolarized mitochondria. As such Nix may represent the closest mammalian homologue of the yeast Atg32, at least in erythroid mitophagy [80]. Figure 7. Schematic representation of the structure of p62 and NBR1 adaptors, and of their binding partners. "
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    • "Mature mammalian erythrocytes are devoid of intracellular organites, and this means that they consist of a single compartment, simplifying many approaches for transport studies. During the end of cellular differentiation, the nucleus is extruded from the normoblats and engulfed by surrounding macrophages (Yoshida et al., 2005), and the other organelles are removed during the maturation of reticulocytes into erythrocytes, probably mainly via autophagy (Kundu et al., 2008; Mortensen et al., 2010). This makes mature erythrocytes from mammals a very easy-touse model for plasma membrane transport studies: intracellular constant measurements (ion or metabolite concentrations, pH) and flux experiments are easier than in any other type of cell containing multiple compartments. "
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