1. MtDNA mutagenesis impairs elimination of mitochondria during erythroid maturation leading to enhanced erythrocyte destruction.
- Author
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Ahlqvist KJ, Leoncini S, Pecorelli A, Wortmann SB, Ahola S, Forsström S, Guerranti R, De Felice C, Smeitink J, Ciccoli L, Hämäläinen RH, and Suomalainen A
- Subjects
- Anemia metabolism, Anemia pathology, Animals, Cell Differentiation, Child, Preschool, DNA Polymerase gamma, DNA, Mitochondrial metabolism, DNA-Directed DNA Polymerase deficiency, DNA-Directed DNA Polymerase genetics, Erythrocytes metabolism, Erythropoiesis genetics, Female, Hematopoietic Stem Cells metabolism, Hematopoietic Stem Cells pathology, Humans, Iron metabolism, Macrophages metabolism, Macrophages pathology, Mice, Mice, Inbred C57BL, Mice, Transgenic, Mitochondria metabolism, Mitochondria pathology, Mitochondrial Diseases metabolism, Mitochondrial Diseases pathology, Oxidative Stress, Phagocytosis, Progeria metabolism, Progeria pathology, Reticulocytes metabolism, Reticulocytes pathology, Anemia genetics, DNA, Mitochondrial genetics, Erythrocytes pathology, Mitochondria genetics, Mitochondrial Diseases genetics, Mutation, Progeria genetics
- Abstract
Haematopoietic progenitor cells show special sensitivity to mitochondrial DNA (mtDNA) mutagenesis, which suggests that increased mtDNA mutagenesis could underlie anemias. Here we show that elevated mtDNA mutagenesis in mice with a proof-reading deficient mtDNA polymerase (PolG) leads to incomplete mitochondrial clearance, with asynchronized iron loading in erythroid precursors, and increased total and free cellular iron content. The resulting Fenton chemistry leads to oxidative damage and premature destruction of erythrocytes by splenic macrophages. Our data indicate that mitochondria actively contribute to their own elimination in reticulocytes and modulate iron loading. Asynchrony of this sequence of events causes severe mitochondrial anaemia by depleting the organism of red blood cells and the bone marrow of iron. Our findings account for the anaemia development in a progeroid mouse model and may have direct relevance to the anemias associated with human mitochondrial disease and ageing.
- Published
- 2015
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