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 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.
Research Programs Unit, Molecular Neurology, University of Helsinki, Biomedicum-Helsinki, Haartmaninkatu 8, FI-00290 Helsinki, Finland.
K J
KJ
Ahlqvist
1] Department of Molecular and Developmental Medicine, University of Siena, I-53100 Siena, Italy [2] Child Neuropsychiatry Unit, University Hospital Azienda Ospedaliera Universitaria Senese, I-53100 Siena, Italy.
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S
Leoncini
1] Department of Molecular and Developmental Medicine, University of Siena, I-53100 Siena, Italy [2] Child Neuropsychiatry Unit, University Hospital Azienda Ospedaliera Universitaria Senese, I-53100 Siena, Italy.
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A
Pecorelli
Nijmegen Centre for Mitochondrial Disorders, Radboud University Medical Center, NL-6500 GA Nijmegen, The Netherlands.
S B
SB
Wortmann
Research Programs Unit, Molecular Neurology, University of Helsinki, Biomedicum-Helsinki, Haartmaninkatu 8, FI-00290 Helsinki, Finland.
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S
Ahola
Research Programs Unit, Molecular Neurology, University of Helsinki, Biomedicum-Helsinki, Haartmaninkatu 8, FI-00290 Helsinki, Finland.
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S
Forsström
Department of Medical Biotechnologies, University of Siena, and Clinical Pathology Laboratory Unit, University Hospital, AOUS, I-53100 Siena, Italy.
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R
Guerranti
Neonatal Intensive Care Unit, University Hospital Azienda Ospedaliera Universitaria Senese, I-53100 Siena, Italy.
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C
De Felice
Nijmegen Centre for Mitochondrial Disorders, Radboud University Medical Center, NL-6500 GA Nijmegen, The Netherlands.
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J
Smeitink
Department of Molecular and Developmental Medicine, University of Siena, I-53100 Siena, Italy.
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L
Ciccoli
Research Programs Unit, Molecular Neurology, University of Helsinki, Biomedicum-Helsinki, Haartmaninkatu 8, FI-00290 Helsinki, Finland.
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RH
Hämäläinen
1] Research Programs Unit, Molecular Neurology, University of Helsinki, Biomedicum-Helsinki, Haartmaninkatu 8, FI-00290 Helsinki, Finland [2] Helsinki University Central Hospital, Department of Neurology, 00290 Helsinki, Finland [3] Neuroscience Center, University of Helsinki, 00290 Helsinki, Finland.
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Suomalainen
D000740:Anemia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D002454:Cell Differentiation; D002675:Child, Preschool; D000074002:DNA Polymerase gamma; D004272:DNA, Mitochondrial / Q000235:genetics* / Q000378:metabolism; D004259:DNA-Directed DNA Polymerase / Q000172:deficiency / Q000235:genetics; D004912:Erythrocytes / Q000378:metabolism / Q000473:pathology*; D004920:Erythropoiesis / Q000235:genetics; D005260:Female; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007501:Iron / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D028361:Mitochondrial Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D018384:Oxidative Stress; D010587:Phagocytosis; D011371:Progeria / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D012156:Reticulocytes / Q000378:metabolism / Q000473:pathology
D004272:DNA, Mitochondrial; D007501:Iron; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase; C498803:Polg protein, mouse