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Mitochondria in Hematopoiesis and Hematological Diseases Oncogene (2006) 25, 4757–4767 & 2006 Nature Publishing Group All rights reserved 0950-9232/06 $30.00 www.nature.com/onc REVIEW Mitochondria in hematopoiesis and hematological diseases M Fontenay1, S Cathelin2, M Amiot3, E Gyan1 and E Solary2 1Inserm U567, Institut Cochin, Department of Hematology, Paris, Cedex, France; 2Inserm U601, Biology Institute, Nantes, Cedex, France and 3Inserm U517, Faculty of Medicine, Dijon, France Mitochondria are involved in hematopoietic cell homeo- Introduction stasis through multiple ways such as oxidative phosphor- ylation, various metabolic processes and the release of As in other tissues, mitochondria play many important cytochrome c in the cytosol to trigger caspase activation roles in hematopoietic cell homeostasis, including the and cell death. In erythroid cells, the mitochondrial steps production of adenosine triphosphate (ATP) by the in heme synthesis, iron (Fe) metabolism and Fe-sulfur process of oxidative phosphorylation, the release of (Fe-S) cluster biogenesis are of particular importance. death-promoting factors upon apoptotic stimuli and a Mutations in the specific d-aminolevulinic acid synthase variety of metabolic pathways such as heme synthesis. (ALAS) 2 isoform that catalyses the first and rate-limiting Mitochondria could also play a role in specific pathways step in heme synthesis pathway in the mitochondrial of hematopoietic cell differentiation through caspase matrix, lead to ineffective erythropoiesis that charac- activation.Alterations of these mitochondrial functions terizes X-linked sideroblastic anemia (XLSA), the most play a pathophysiological role in a variety of hemato- common inherited sideroblastic anemia. Mutations in the logical diseases, especially those affecting erythroid adenosine triphosphate-binding cassette protein ABCB7, lineage such as inherited dyserythropoiesis and side- identified in XLSA with ataxia (XLSA-A), disrupt the roblastic anemias and acquired, low-grade myelodys- maturation of cytosolic (Fe-S) clusters, leading to plastic syndromes.In these diseases, compromised mitochondrial Fe accumulation. In addition, large dele- mitochondrial functions could be related to mitochon- tions in mitochondrial DNA, whose integrity depends on a drial genome mutations, alterations in iron (Fe) specific DNA polymerase, are the hallmark of Pearson’s mitochondrial metabolism or exacerbation of physio- syndrome, a rare congenital disorder with sideroblastic logical pathways involving caspases, leading to activa- anemia. In acquired myelodysplastic syndromes at early tion of the mitochondrial pathway to apoptotic cell stage, exacerbation of physiological pathways involving death.Mitochondria also plays a central role in the caspases and the mitochondria in erythroid differentiation apoptotic response of transformed hematopoietic cells leads to abnormal activation of a mitochondria-mediated when exposed to cytotoxic drugs, although oncogenesis- apoptotic cell death pathway. In contrast, oncogenesis- associated changes at the mitochondrial level can induce associated changes at the mitochondrial level can alter the resistance to apoptosis induced by a variety of these apoptotic response of transformed hematopoietic cells to drugs.Owing to their central role in cell death, chemotherapeutic agents. Recent findings in mitochondria mitochondria now appear as a potential target for metabolism and functions open new perspectives in killing malignant cells.This review will evoke several treating hematopoietic cell diseases, for example various examples in which mitochondria play a pathophysio- compounds currently developed to trigger tumor cell death logical role in hematopoietic diseases, the role of these by directly targeting the mitochondria could prove organelles in hematopoietic cell differentiation and efficient as either cytotoxic drugs or chemosensitizing response to cytotoxic agents and the various strategies agents in treating hematological malignancies. currently tested to use mitochondria as a target to treat Oncogene (2006) 25, 4757–4767. doi:10.1038/sj.onc.1209606 malignant hematopoietic diseases. Keywords: mitochondria; sideroblastic anemia; leukemia; myelodysplastic syndromes; apoptosis Mitochondrial DNA mutations in hematopoietic cell aging and diseases Together with the nucleus, mitochondria are the only organelles of animal cells that contain DNA as well as their own machinery for RNA and protein synthesis. Mitochondrial DNA (mtDNA) is a double-stranded circular molecule present as 2–10 copies in each Correspondence: Dr E Solary, UMR Inserm 517, Faculty of Medicine, mitochondrion.Cells contain thousands of mtDNA mole- 7, boulevard Jeanne d’Arc, Dijon 21000, France. cules that distinguish from nuclear DNA (nDNA) by E-mail: [email protected] several characteristics, including maternal inheritance, Mitochondria in hematopoiesis and hematological diseases M Fontenay et al 4758 a modified genetic code, a paucity of introns, the lack of Table 1 Main genetic hematological diseases related to mitochondria histone protection and the limited efficacy of the repair alterations system.These two later characteristics, together with its Disease Genetic alterations proximity to radical oxygen species (ROS) generation due to oxidative phosphorylation for ATP production, Pearson’s syndrome Large deletions in mtDNA X-linked sideroblastic anemia ALAS2 may account to the 10- to 20-fold higher mutation rate X-linked sideroblastic anemia ABCB7 gene mutation (Atm1p in mtDNA compared with nDNA (Yakes and Van with ataxia in yeast) Houten, 1997).In addition, multiple species of mtDNA Friedreich ataxia Frataxin gene mutations can coexist in a single cell, a condition called hetero- Kostmann’s syndrome Decreased Bcl-2 expression plasmy. Animal models of sideroblastic Flexed-tail mutation, SOD2 anemia deletion Somatically acquired mtDNA mutations are attribu- table to mitochondrial oxidative damage, which in- Abbreviations: mtDNA: mitochondrial DNA; ALAS: d-amino- creases with age.Single mutant mtDNA molecules have levulinic acid synthase 2; SOD2: superoxide dismutase-2. long been assumed to be lost by dilution in rapidly dividing tissues such as bone marrow.Actually, age- dependent accumulation of mtDNA mutations, and expansion of mutated mtDNA molecules from hetero- plasmy to homoplasmy (Chinnery et al., 2002), appear to be relatively common in adult CD34 þ marrow progenitors and presumably stem cells (Ogasawara et al., 2005). Thus, age-associated mtDNA mutations lead to marked heterogeneity among adult bone marrow and peripheral blood CD34 þ cells, not present in umbilical cord blood.Mitochondrial DNA variant sequences were proposed as natural genetic markers for determining the contribution of individual stem cells Figure 1 Ring sideroblasts.( a) Perls staining showing a ring to blood production.In addition, mtDNA changes fixed sideroblast due to iron (Fe) overload in the mitochondria forming a ring around the nucleus in basophilic and polychromatophilic in leukemic cells might provide a simple method for erythroblasts.( b and c) Electron microscopy analysis of apoptotic monitoring minimal residual disease (He et al., 2003). ring sideroblasts (mi: mitochondrion). Integrity of mtDNA involves a DNA polymerase whose catalytic subunit is encoded by a nuclear gene. Knock-in mice that express a proof-reading-deficient mutations were identified in the genes encoding the version of the catalytic subunit of this polymerase develop mitochondrial tRNA for leucine, the subunit I of a MtDNA mutator phenotype with a significant increase cytochrome c oxidase and the cytochrome b (Gattermann in the level of point mutations, as well as increased et al., 1996, 1997; Reddy et al., 2002). The link between amounts of deletions.These events are associated with these mutations and the disease remains highly con- reduced lifespan and premature onset of aging-related troversial as a comparative study did not demonstrate an symptoms, including anemia (Trifunovic et al., 2004). increase in the frequency of mtDNA mutations in a large Interestingly, the increase in mtDNA mutations observed cohort of myelodysplastic syndrome patients compared in these mice does not depend on an increase in oxidative to age-matched normal individuals (Shin et al., 2003). phosphorylation (Kujoth et al.,2005). A current speculation is that age-related mtDNA Lesions in mtDNA and mitochondrial dysfunction mutations in CD34 þ clones could lead to derangement contribute to numerous human diseases.Large deletions of marrow function in older individuals (Shin et al., in mtDNA are the hallmark of Pearson’s syndrome, a 2004).Whether these mutations are associated with rare congenital disorder with lactic acidosis, pancreatic abnormal oxidative phosphorylation measured in mye- insufficiency and sideroblastic anemia (Pearson et al., lodysplastic syndrome bone-marrow samples is a matter 1979; Rotig et al., 1991) (Table 1). Sideroblastic anemias of discussion (Bowen and Peddie, 2002; Matthes et al., are characterized by Fe overload in the mitochondria 2002).At least in older patients, they could also play a that are revealed by Perls staining as a ring around the role in excessive apoptosis that characterizes low-grade nucleus in basophilic and polychromatophilic erythro- myelodysplastic syndromes (Bouscary et al., 1997) as blasts (Figure 1).Transmission electron microscopy mice with defective mtDNA polymerase exhibit apop- analysis of bone-marrow cells in infants with inherited tosis in excess in several rapidly growing tissues (Kujoth sideroblastic
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