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

Nature Communications
K J AhlqvistA Suomalainen

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.

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Citations

May 28, 2015·Biochimica Et Biophysica Acta·Kati J AhlqvistRiikka H Hämäläinen
May 23, 2015·Nature·Anu Suomalainen
Aug 5, 2016·Cell and Tissue Research·Jörn Dengjel, Hagai Abeliovich
Mar 28, 2018·Genes·Tianhong SuLaura C Greaves
Sep 3, 2017·Journal of Inherited Metabolic Disease·Omar HikmatLaurence A Bindoff
Dec 28, 2018·Pediatric Blood & Cancer·Marketa TesarovaJiri Zeman
Aug 10, 2017·Nature Reviews. Molecular Cell Biology·Anu Suomalainen, Brendan J Battersby
Jan 10, 2018·Frontiers in Physiology·Martina MorasMariano A Ostuni
Aug 7, 2018·The Journal of Clinical Investigation·Miranda K Culley, Stephen Y Chan
Sep 27, 2018·Proceedings of the National Academy of Sciences of the United States of America·Timo E S KauppilaNils-Göran Larsson
Mar 12, 2021·Biochemistry. Biokhimii︠a︡·K G LyamzaevB V Chernyak
Oct 6, 2020·Fish & Shellfish Immunology·Minxuan YangZhendong Qin
Jun 12, 2021·Disease Models & Mechanisms·Marlies P RossmannLeonard I Zon

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