Although deletion of certain autophagy-related genes has been associated with defects in hematopoiesis, it remains unclear whether hyperactivated mitophagy affects the maintenance and differentiation of hematopoietic stem cells (HSCs) and committed progenitor cells. Here we report that targeted deletion of the gene encoding the AAA+-ATPase Atad3a hyperactivated mitophagy in mouse hematopoietic cells. Affected mice showed reduced survival, severely decreased bone-marrow cellularity, erythroid anemia and B cell lymphopenia. Those phenotypes were associated with skewed differentiation of stem and progenitor cells and an enlarged HSC pool. Mechanistically, Atad3a interacted with the mitochondrial channel components Tom40 and Tim23 and served as a bridging factor to facilitate appropriate transportation and processing of the mitophagy protein Pink1. Loss of Atad3a caused accumulation of Pink1 and activated mitophagy. Notably, deletion of Pink1 in Atad3a-deficient mice significantly 'rescued' the mitophagy defect, which resulted in restoration of the progenitor and HSC pools. Our data indicate that Atad3a suppresses Pink1-dependent mitophagy and thereby serves a key role in hematopoietic homeostasis.

中文翻译：

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Atad3a抑制Pink1依赖性线粒体维持造血祖细胞的稳态。

尽管某些自噬相关基因的缺失与造血功能缺陷有关，但尚不清楚超活化的丝噬体是否影响造血干细胞（HSC）和定型祖细胞的维持和分化。在这里，我们报道了小鼠造血细胞中编码AAA + -ATPase Atad3a的超活化线粒体基因的靶向缺失。患病小鼠表现出降低的存活率，严重降低的骨髓细胞性，类红细胞性贫血和B细胞淋巴细胞减少症。这些表型与干细胞和祖细胞的偏向分化以及扩大的HSC库有关。从机制上讲，Atad3a与线粒体通道成分Tom40和Tim23相互作用，并作为桥接因子，促进线粒体蛋白Pink1的适当运输和加工。Atad3a的丢失会导致Pink1的积累并激活线粒体。值得注意的是，在Atad3a缺陷型小鼠中删除Pink1可以显着“挽救”线粒体缺陷，从而导致祖细胞和HSC池的恢复。我们的数据表明，Atad3a抑制Pink1依赖性线粒体，从而在造血稳态中发挥关键作用。