SCIENCE@home

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

K. Ahlqvist,S. Leoncini,A. Pecorelli,S. Wortmann,S. Ahola,S. Forsström,R. Guerranti,C. De Felice,J. Smeitink,L. Ciccoli,R. Hämäläinen,A. Suomalainen

Published 2015 in Nature Communications

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. 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.

PUBLICATION RECORD

CITATION MAP

EXTRACTION MAP

CLAIMS

  • No claims are published for this paper.

CONCEPTS

  • No concepts are published for this paper.

REFERENCES

Showing 1-56 of 56 references · Page 1 of 1

CITED BY

Showing 1-65 of 65 citing papers · Page 1 of 1