MtDNA mutagenesis impairs elimination of mitochondria during erythroid maturation leading to enhanced erythrocyte destruction
MtDNA mutagenesis impairs elimination of mitochondria during erythroid maturation leading to enhanced erythrocyte destruction
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DOI：
10.1038/ncomms7494
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发表时间：
2015-03-01
影响因子：
16.6
通讯作者：
Suomalainen, A.
中科院分区：
文献类型：
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作者：
Ahlqvist, K. J.;Leoncini, S.;Suomalainen, A.
造血祖细胞对线粒体DNA（mtDNA）突变表现出特殊的敏感性，这表明增加的mtDNA突变可能是贫血的基础。在这里，我们表明，在小鼠与校正缺陷的mtDNA聚合酶（PolG）的mtDNA突变升高，导致线粒体清除不完全，在红细胞前体铁负载，并增加总的和游离的细胞铁含量。由此产生的芬顿化学导致氧化损伤和脾巨噬细胞对红细胞的过早破坏。我们的数据表明，线粒体积极地促进其自身在网织红细胞中的消除并调节铁负荷。这一系列事件的不同步通过消耗有机体的红细胞和骨髓的铁而导致严重的线粒体贫血。我们的研究结果解释了早衰小鼠模型中的贫血发展，并可能与人类线粒体疾病和衰老相关的贫血直接相关。
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.