Enhanced programmed cell death of iron-deficient erythrocytes.
Exposure of erythrocytes to osmotic shock, oxidative stress, and energy depletion activates Cl--sensitive and Ca2+-permeable cation channels. Subsequent Ca2+ entry triggers eryptosis, characterized by erythrocyte shrinkage, membrane blebbing, and phosphatidylserine exposure all features typical for apoptotic death of nucleated cells. Erythrocytes exposing phosphatidylserine are recognized, bound, engulfed, and degraded by macrophages. Eryptosis thus fosters clearance of affected erythrocytes from circulating blood. Iron deficiency leads to anemia, in part by decreasing erythrocyte life span. In this study, phosphatidylserine exposure, cell size, and cytosolic Ca2+ were measured by FACS analysis of annexin-V binding, forward scatter, and Fluo-3 fluorescence, respectively. Erythrocytes from mice on control diet were compared with erythrocytes from mice exposed 10 weeks to iron-deficient diet. Iron deficiency significantly (P<0.001) enhanced erythrocyte annexin-V binding (from 2.4 to 3.7%), decreased forward scatter (from 544 to 393), and increased cytosolic Ca2+ concentration. 45Ca2+ flux measurements and patch clamp experiments revealed enhanced Ca2+ uptake (by 2.3-fold) and cation channel activity. The half-life of fluorescence-labeled, iron-deficient, or Ca2+-loaded erythrocytes was significantly reduced compared with control erythrocytes. Thus, the experiments reveal a novel mechanism triggered by iron deficiency, which presumably contributes to accelerated clearance of erythrocytes in iron deficiency anemia.
Kempe
Daniela S
DS
Department of Physiology, University of Tübingen, Tübingen, Germany.
Lang
Philipp A
PA
Duranton
Christophe
C
Akel
Ahmad
A
Lang
Karl S
KS
Huber
Stephan M
SM
Wieder
Thomas
T
Lang
Florian
F
D018798:Anemia, Iron-Deficiency / Q000097:blood* / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D002118:Calcium / Q000378:metabolism; D048429:Cell Size; D003600:Cytosol / Q000378:metabolism; D004912:Erythrocytes / Q000166:cytology* / Q000473:pathology; D005260:Female; D006207:Half-Life; D007473:Ion Channels / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010718:Phosphatidylserines / Q000378:metabolism
D007473:Ion Channels; D010718:Phosphatidylserines; D002118:Calcium