title: Erythroid precursors from patients with low-risk myelodysplasia demonstrate ultrastructural features of enhanced autophagy of mitochondria.
abstract: Recent studies in erythroid cells have shown that autophagy is an important process for the physiological clearance of mitochondria during terminal differentiation. However, autophagy also plays an important role in removing damaged and dysfunctional mitochondria. Defective mitochondria and impaired erythroid maturation are important characteristics of low-risk myelodysplasia. In this study we therefore questioned whether the autophagic clearance of mitochondria might be altered in erythroblasts from patients with refractory anemia (RA, n=3) and RA with ringed sideroblasts (RARS, n=6). Ultrastructurally, abnormal and iron-laden mitochondria were abundant, especially in RARS patients. A large proportion (52+/-16%) of immature and mature myelodysplastic syndrome (MDS) erythroblasts contained cytoplasmic vacuoles, partly double membraned and positive for lysosomal marker LAMP-2 and mitochondrial markers, findings compatible with autophagic removal of dysfunctional mitochondria. In healthy controls only mature erythroblasts comprised these vacuoles (12+/-3%). These findings were confirmed morphometrically showing an increased vacuolar surface in MDS erythroblasts compared to controls (P<0.0001). In summary, these data indicate that MDS erythroblasts show features of enhanced autophagy at an earlier stage of erythroid differentiation than in normal controls. The enhanced autophagy might be a cell protective mechanism to remove defective iron-laden mitochondria.
authors.affiliation: Department of Hematology, University Medical Center Groningen, Groningen, The Netherlands. e.j.houwerzijl@int.umcg.nl
authors.forename: E J
authors.initials: EJ
authors.lastname: Houwerzijl
authors.forename: H-W D
authors.initials: HW
authors.lastname: Pol
authors.forename: N R
authors.initials: NR
authors.lastname: Blom
authors.forename: J J L
authors.initials: JJ
authors.lastname: van der Want
authors.forename: J Th M
authors.initials: JT
authors.lastname: de Wolf
authors.forename: E
authors.initials: E
authors.lastname: Vellenga
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000753:Anemia, Refractory / Q000378:metabolism / Q000473:pathology*; D000756:Anemia, Sideroblastic / Q000378:metabolism / Q000473:pathology*; D001343:Autophagy; D016022:Case-Control Studies; D053148:Caspase 3; D002454:Cell Differentiation; D004789:Enzyme Activation; D004900:Erythroblasts / Q000378:metabolism / Q000648:ultrastructure*; D015672:Erythroid Precursor Cells / Q000378:metabolism / Q000648:ultrastructure*; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D052119:Lysosomal-Associated Membrane Protein 2; D051907:Lysosomal Membrane Proteins / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000648:ultrastructure*; D012307:Risk Factors
chemical_list: C497811:LAMP2 protein, human; D052119:Lysosomal-Associated Membrane Protein 2; D051907:Lysosomal Membrane Proteins; D053148:Caspase 3