Atad3a suppresses Pink1-dependent mitophagy to maintain homeostasis of hematopoietic progenitor cells.
Atad3a suppresses Pink1-dependent mitophagy to maintain homeostasis of hematopoietic progenitor cells.
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DOI：
10.1038/s41590-017-0002-1
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发表时间：
2018-01
影响因子：
30.5
通讯作者：
Lin HK
中科院分区：
文献类型：
--
作者：
Jin G;Xu C;Zhang X;Long J;Rezaeian AH;Liu C;Furth ME;Kridel S;Pasche B;Bian XW;Lin HK
尽管某些自噬相关基因的缺失与造血缺陷有关，但过度激活的有丝分裂吞噬是否影响造血干细胞(HSCs)和定向祖细胞的维持和分化仍不清楚。在此，我们报道了编码AAA+-ATPase Atad3a高活性有丝分裂吞噬的基因在小鼠造血细胞中的定向缺失。受影响的小鼠存活率降低，骨髓细胞数严重减少，红细胞性贫血和B细胞减少。这些表型与干细胞和祖细胞的偏向分化以及HSC池的扩大有关。在机制上，Atad3a与线粒体通道组件Tom40和TIM23相互作用，并作为桥梁因子促进有丝分裂蛋白PINK1的适当运输和加工。Atad3a的缺失导致PINK1的积聚和激活的有丝分裂。值得注意的是，在Atad3a基因缺陷的小鼠中，PINK1的缺失显著地‘挽救了’有丝分裂缺陷，这导致了祖细胞和HSC池的恢复。我们的数据表明，Atad3a抑制PINK1依赖的有丝分裂吞噬，从而在造血动态平衡中发挥关键作用。
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.
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DOI：
10.1083/jcb.201008084
发表时间：
2010-11-29
期刊：
The Journal of cell biology
影响因子：
--
作者：
Jin SM;Lazarou M;Wang C;Kane LA;Narendra DP;Youle RJ
通讯作者：
Youle RJ
影响因子：
64.5
作者：
Kiel, MJ;Yilmaz, ÖH;Morrison, SJ
通讯作者：
Morrison, SJ
影响因子：
20.3
作者：
Liu, Fei;Lee, Jae Y.;Guan, Jun-Lin
通讯作者：
Guan, Jun-Lin
影响因子：
5.3
作者：
Gilquin, Benoit;Taillebourg, Emmanuel;Baudier, Jacques
通讯作者：
Baudier, Jacques
DOI：
10.1083/jcb.200910140
发表时间：
2010-04-19
期刊：
The Journal of cell biology
影响因子：
--
作者：
Matsuda N;Sato S;Shiba K;Okatsu K;Saisho K;Gautier CA;Sou YS;Saiki S;Kawajiri S;Sato F;Kimura M;Komatsu M;Hattori N;Tanaka K
通讯作者：
Tanaka K