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.
Highlights
Haematopoietic progenitor cells show special sensitivity to mitochondrial DNA mutagenesis, which suggests that increased mtDNA mutagenesis could underlie anemias
We show that mtDNA mutagenesis affects mitochondrial removal during erythroid development indicating that signals intrinsic to mitochondria contribute to red blood cell maturation
We show that reactive oxygen species (ROS)/redox signalling in erythroid maturation affects transferrinmediated iron loading that in turn leads to an increase of total and non-protein-bound iron (NPBI) in the peripheral blood of these animals
Summary
Haematopoietic progenitor cells show special sensitivity to mitochondrial DNA (mtDNA) mutagenesis, which suggests that increased mtDNA mutagenesis could underlie anemias. 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. Anaemia is a manifestation of the progeroid mtDNA mouse model known as the ‘Mutator’, which harbours a proof-reading deficient mtDNA polymerase gamma (PolG) that leads to increased random mtDNA mutagenesis in all cell types, including somatic stem cells (SSCs)[7,8,9] These mice show aberrant hematopoiesis that initiates in embryogenesis and is progressive, developing anaemia and leucopenia after 6 months of age restricting their lifespan to about 50 weeks of age[9]. Exposure of PS on the erythrocyte surfaces acts as a signal for splenic macrophages to capture and destroy old erythrocytes[28] thereby contributing to anaemia
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