title: Different pathophysiological mechanisms of intramitochondrial iron accumulation in acquired and congenital sideroblastic anemia caused by mitochondrial DNA deletion.
abstract: Sideroblastic anemias (SA) are characterized by iron accumulation in the mitochondria of erythroblasts. Although we have evidence of mitochondrial gene alterations in sporadic congenital cases, the origin of acquired forms [refractory anemia with ring sideroblasts (RARS)], is still largely unknown. Here, we report the analysis of respiratory chain function in a patient with a large mitochondrial deletion and in patients with RARS. A young boy with SA showed symptoms typical of a mitochondrial disease with metabolic acidosis, muscle weakness and cerebral involvement. His bone marrow DNA was analyzed for the presence of mitochondrial deletions. We found a new mitochondrial (mt)DNA deletion spanning 3,614 bp and including all the mt genes encoding complex IV, plus ATPase 6 and 8, and several transfer (t)RNAs. All tissues analyzed (liver, skeletal muscle, brain, pancreas) showed a heteroplasmic distribution of this mutant DNA. Bone marrow homogenates were obtained from five patients with RARS and from three patients with normal bone marrow and respiratory chain function assayed by spectrophotometric analysis. Cytochrome c oxidase (CCO) activity was greatly reduced in the patient's bone marrow. In contrast, CCO activity and global respiratory chain function were conserved in patients with RARS. We conclude that deficient CCO activity secondary to mtDNA deletions is related to intramitochondrial iron accumulation, as in our patient or in those with Pearson's syndrome, whereas other mechanisms, e.g. nuclear DNA mutations, have to be proposed to be involved in the acquired forms of SA.
authors.affiliation: Department of Internal Medicine, Unit of Clinical Hematology, University Hospital, Geneva, Switzerland. thomas.matthes@hcuge.ch
authors.forename: Thomas
authors.initials: T
authors.lastname: Matthes
authors.forename: Pierre
authors.initials: P
authors.lastname: Rustin
authors.forename: Hedwige
authors.initials: H
authors.lastname: Trachsel
authors.forename: Régis
authors.initials: R
authors.lastname: Darbellay
authors.forename: S
authors.initials: S
authors.lastname: Costaridou
authors.forename: A
authors.initials: A
authors.lastname: Xaidara
authors.forename: Alexandra
authors.initials: A
authors.lastname: Rideau
authors.forename: Photis
authors.initials: P
authors.lastname: Beris
mesh_terms: D000138:Acidosis / Q000235:genetics; D000293:Adolescent; D000753:Anemia, Refractory / Q000235:genetics; D000756:Anemia, Sideroblastic / Q000235:genetics / Q000378:metabolism*; D001853:Bone Marrow / Q000473:pathology; D030401:Cytochrome-c Oxidase Deficiency / Q000235:genetics*; D004252:DNA Mutational Analysis; D004272:DNA, Mitochondrial / Q000235:genetics*; D018450:Disease Progression; D004579:Electron Transport; D003576:Electron Transport Complex IV / Q000032:analysis / Q000235:genetics*; D017809:Fatal Outcome; D017353:Gene Deletion; D006579:Heterozygote; D006801:Humans; D007501:Iron / Q000378:metabolism*; D008297:Male; D008928:Mitochondria / Q000378:metabolism*; D017240:Mitochondrial Myopathies / Q000097:blood / Q000235:genetics*; D025261:Mitochondrial Proton-Translocating ATPases / Q000172:deficiency* / Q000235:genetics; D009030:Mosaicism; D012343:RNA, Transfer / Q000235:genetics; D017086:beta-Thalassemia / Q000235:genetics
chemical_list: D004272:DNA, Mitochondrial; D012343:RNA, Transfer; D007501:Iron; D003576:Electron Transport Complex IV; C412204:ATP synthase subunit 6; C513300:MT-ATP8 protein, human; D025261:Mitochondrial Proton-Translocating ATPases