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 and A. Suomalainen ()
Additional contact information
K.J. Ahlqvist: Research Programs Unit, Molecular Neurology, University of Helsinki, Biomedicum-Helsinki, Haartmaninkatu 8, FI-00290 Helsinki, Finland
S. Leoncini: University of Siena
A. Pecorelli: University of Siena
S.B. Wortmann: Nijmegen Centre for Mitochondrial Disorders, Radboud University Medical Center
S. Ahola: Research Programs Unit, Molecular Neurology, University of Helsinki, Biomedicum-Helsinki, Haartmaninkatu 8, FI-00290 Helsinki, Finland
S. Forsström: Research Programs Unit, Molecular Neurology, University of Helsinki, Biomedicum-Helsinki, Haartmaninkatu 8, FI-00290 Helsinki, Finland
R. Guerranti: University of Siena, and Clinical Pathology Laboratory Unit, University Hospital, AOUS
C. De Felice: Neonatal Intensive Care Unit, University Hospital Azienda Ospedaliera Universitaria Senese
J. Smeitink: Nijmegen Centre for Mitochondrial Disorders, Radboud University Medical Center
L. Ciccoli: University of Siena
R.H. Hämäläinen: Research Programs Unit, Molecular Neurology, University of Helsinki, Biomedicum-Helsinki, Haartmaninkatu 8, FI-00290 Helsinki, Finland
A. Suomalainen: Research Programs Unit, Molecular Neurology, University of Helsinki, Biomedicum-Helsinki, Haartmaninkatu 8, FI-00290 Helsinki, Finland

Nature Communications, 2015, vol. 6, issue 1, 1-11

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms7494

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