www.landesbioscience.com Cell Cycle 1901
Cell Cycle 9:10, 1901-1906; May 15, 2010; © 2010 Landes Bioscience
Key words: autophagy, Nix, Ulk1, Atg7,
erythrocyte, mitochondria, anemia,
Abbreviations: BM, bone marrow;
MOMP, mitochondrial outer membrane
permeabilisation; RBC, red blood cell;
ROS, reactive oxygen species; PE, phos-
phatidylethanolamine; Ptds, phosphati-
Previously published online:
*Correspondence to: Anna Katharina Simon;
the nucleus from erythroblasts leads to
the formation of reticulocytes, which
still contain organelles. The mecha-
nisms responsible for the final removal
of organelles from developing eryth-
roid cells are still being elucidated.
Mitochondria are the most abundant
organelles to be cleared for the comple-
tion of erythropoiesis. Macroautophagy,
referred to as autophagy, is a regu-
lated 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 mito-
chondria (mitophagy) as a possible
mechanism for mitochondrial clearance
in these. Recently, a number of stud-
ies 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 clear-
ance from developing erythroid cells.
Importantly, however, the extent to
which the absence of mitophagy affects
erythroid development differs depend-
ing on the model and gene investi-
gated. This review will therefore focus
on comparing the different studies of
mitophagy in erythroid development
and highlight some of the remaining
rythrocytes are anucleated cells
devoid of organelles. Expulsion of
Red Blood Cell Maturation
Involves the Removal
Erythrocytes differentiate from hematopoi-
etic stem cells in the bone marrow (BM).1
Erythroblastic islands, niches for eryth-
roid differentiation, are found in fetal
liver, spleen and BM. These islands consist
of a central macrophage surrounded by at
least one synchronously maturing cohort
of erythroid cells.2 The pronormoblast,
earliest recognisable erythroid precur-
sor, divides and gives rise to increasingly
smaller normoblasts around the central
macrophage. Normoblasts contain pro-
gressively less RNA but more hemoglo-
bin and more condensed chromatin. The
nucleus is finally extruded from the late-
normoblast and displays phosphatidylser-
ine (Ptds) on its surface, which triggers its
phagocytosis by the erythroblastic island’s
macrophage.3 An anucleated reticulocyte
results and exits the BM, circulates in
peripheral blood for a couple of days and
then matures, mostly in the spleen, into an
erythrocyte.1 Reticulocytes retain mito-
chondria, endocytic vesicles, ribosomes,
golgi cisternae and rough endoplasmic
reticulum (ER).4 These organelles are then
lost as reticulocytes mature into eryth-
rocytes.5 Until recently, the mechanisms
by which these organelles are removed
remained unclear. An accumulation of
autophagosomes was observed in early
electron micrographs of human peripheral
blood cells,6 as well as in rat erythroblasts
and reticulocytes.7 This led to the sug-
gestion that autophagy could be one such
mechanism, responsible for the removal
Mitochondrial clearance by autophagy in developing erythrocytes
Clearly important, but just how much so?
Monika Mortensen,1 David J.P. Ferguson2 and Anna Katharina Simon1,3,*
1Nuffield Department of Medicine; Weatherall Institute of Molecular Medicine; 2Nuffield Department of Clinical Laboratory Sciences;
and 3National Institute for Health Research Biomedical Research Centre; John Radcliffe Hospital; Oxford, UK
1906 Cell Cycle volume 9 issue 10
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in any particular setting. Secondly, the
differences observed between the fetal
liver chimera and Vav-Cre models for
hematopoietic-specific gene ablation have
important implications for the interpreta-
tion of future studies using fetal liver or
BM chimeras. Finally, it is envisageable
that more cell- and/or organelle-specific
pathways for autophagosomal degrada-
tion may be discovered. Autophagy being
implicated in a vast number of diseases,
such as neurodegenerative disorders,
infections, cancer and autoimmunity, it is
essential to understand which autophagy
pathway is predominant in each tissue and
under which conditions it is induced. This
will help to achieve a targeted modulation
We would like to thank Owen Williams
for discussions and Tim Hunt for encour-
aging us to carry out this work, which lay
outside our field of expertise. The salary
of M.M. was supported by the Andrew
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