MtDNA mutagenesis impairs elimination of mitochondria during erythroid maturation leading to enhanced erythrocyte destruction

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...

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Bibliographic Details
Published in:	Nature communications Vol. 6; no. 1; p. 6494
Main Authors:	Ahlqvist, K.J., Leoncini, S., Pecorelli, A., Wortmann, S.B., Ahola, S., Forsström, S., Guerranti, R., De Felice, C., Smeitink, J., Ciccoli, L., Hämäläinen, R.H., Suomalainen, A.
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 09-03-2015 Nature Publishing Group
Subjects:	13/100 13/31 13/51 14/1 14/19 14/28 631/208/191/1908 631/80/642/333 64/60 692/308/1426 692/699/1541/13 82/1 Anemia - genetics Anemia - metabolism Anemia - pathology Animals Cell Differentiation Child, Preschool DNA Polymerase gamma DNA, Mitochondrial - genetics DNA, Mitochondrial - metabolism DNA-Directed DNA Polymerase - deficiency DNA-Directed DNA Polymerase - genetics Erythrocytes - metabolism Erythrocytes - pathology Erythropoiesis - genetics Female Hematopoietic Stem Cells - metabolism Hematopoietic Stem Cells - pathology Humanities and Social Sciences Humans Iron - metabolism Macrophages - metabolism Macrophages - pathology Mice Mice, Inbred C57BL Mice, Transgenic Mitochondria - genetics Mitochondria - metabolism Mitochondria - pathology Mitochondrial Diseases - genetics Mitochondrial Diseases - metabolism Mitochondrial Diseases - pathology multidisciplinary Mutation Oxidative Stress Phagocytosis Progeria - genetics Progeria - metabolism Progeria - pathology Reticulocytes - metabolism Reticulocytes - pathology Science Science (multidisciplinary)
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Summary:	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. Accumulation of mitochondrial DNA (mtDNA) mutations is linked to severe anaemia by an unknown mechanism. Here the authors show that excessive mtDNA mutations impair mitochondrial expulsion during erythropoiesis leading to augmented erythrocyte clearance and anaemia in mice and humans.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2041-1723 2041-1723
DOI:	10.1038/ncomms7494