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

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

doi:10.1038/ncomms7494

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

Nat Commun. 2015 Mar 9:6:6494. doi: 10.1038/ncomms7494.

Authors

K J Ahlqvist¹, S Leoncini², A Pecorelli², S B Wortmann³, S Ahola¹, S Forsström¹, R Guerranti⁴, C De Felice⁵, J Smeitink³, L Ciccoli⁶, R H Hämäläinen¹, A Suomalainen⁷

Affiliations

¹ Research Programs Unit, Molecular Neurology, University of Helsinki, Biomedicum-Helsinki, Haartmaninkatu 8, FI-00290 Helsinki, Finland.
² 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.
³ Nijmegen Centre for Mitochondrial Disorders, Radboud University Medical Center, NL-6500 GA Nijmegen, The Netherlands.
⁴ Department of Medical Biotechnologies, University of Siena, and Clinical Pathology Laboratory Unit, University Hospital, AOUS, I-53100 Siena, Italy.
⁵ Neonatal Intensive Care Unit, University Hospital Azienda Ospedaliera Universitaria Senese, I-53100 Siena, Italy.
⁶ Department of Molecular and Developmental Medicine, University of Siena, I-53100 Siena, Italy.
⁷ 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.

PMID: 25751021
DOI: 10.1038/ncomms7494

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

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
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
Mutation*
Oxidative Stress
Phagocytosis
Progeria / genetics*
Progeria / metabolism
Progeria / pathology
Reticulocytes / metabolism
Reticulocytes / pathology

Substances

DNA, Mitochondrial
Iron
DNA Polymerase gamma
DNA-Directed DNA Polymerase
Polg protein, mouse