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 ¼ 3) and RA with ringed sideroblasts (RARS, n ¼ 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 (Po0.0001). 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.

Global transcriptome analyses of human and murine terminal erythroid differentiation

“…[48][49][50] Another important use for these data sets is to develop a better mechanistic understanding of disordered erythropoiesis, with the ability to better understand stage-specific defects. This includes disorders such as the thalassemia syndromes, bone marrow failure syndromes and aplastic anemia [51][52][53][54][55][56] as well as acquired disorders such as the myelodysplasia syndromes, [57][58][59] particularly subtypes with disordered terminal erythroid differentiation. Numerous abnormalities have been identified in these disorders, including perturbed apoptosis, cytokine signaling, and regulation of cellular growth.…”

“…Numerous abnormalities have been identified in these disorders, including perturbed apoptosis, cytokine signaling, and regulation of cellular growth. 57,[60][61][62][63] Comparative analyses between wild-type and variant cells may provide insight into disease pathobiology, allowing understanding of mechanisms of abnormal erythropoiesis over time in specific diseases, and may provide insights into identification of potential therapeutic targets.…”

Mitophagy in hematopoietic stem cells

“…144,145 Ultrastructural studies show increased numbers of autophagosomes and lysosomes containing mitochondria in early erythroblasts of patients with low-risk MDS and enlarged, abnormal mitochondria with iron accumulation and absence of apoptosis in patients with high-risk disease and transfusion dependency. 146,147 These findings suggest that mitochondrial damage may be mitigated by autophagy in low-risk MDS and that disease progression occurs as the ability of cells to eliminate damaged mitochondria is exceeded, leading to increased cell death (and transfusion dependence), and in some cases, to the emergence of clones able to overcome the apoptotic pressure (i.e., AML). Thus, a disruption in the balance between forces promoting mitochondrial damage and the ability of cells to eliminate damaged mitochondria by autophagy may contribute to disease pathogenesis and progression in a subset of patients with MDS.…”

Autophagy in the pathogenesis of myelodysplastic syndrome and acute myeloid leukemia

“…In other words, functional (those less likely to progress to AML, as compared to high-risk patients) display increased numbers of mitochondria-laden autophagosomes. 42 The authors hypothesize that this increase could indicate intrinsic differentiation defects or could be a response to the higher levels of dysfunctional, iron-saturated mitochondria. However it may also be an indication of a positive feedback cycle consisting of mitophagy defects in hematopoietic stem or progenitor cells leading to improper degradation of targeted mitochondria, promoting increased ROS levels that cause DNA damage.…”