Jin Guoxiang, Xu Chuan, Zhang Xian, Long Jie, Rezaeian Abdol Hossein, Liu Chunfang, Furth Mark E, Kridel Steven, Pasche Boris, Bian Xiu-Wu, Lin Hui-Kuan
Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China.
Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC, USA.
Nat Immunol. 2018 Jan;19(1):29-40. doi: 10.1038/s41590-017-0002-1. Epub 2017 Nov 21.
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.
虽然某些自噬相关基因的缺失与造血缺陷有关，但目前尚不清楚过度激活的线粒体自噬是否会影响造血干细胞（HSC）和定向祖细胞的维持与分化。在此，我们报告编码AAA + -ATP酶Atad3a的基因在小鼠造血细胞中的靶向缺失会过度激活线粒体自噬。受影响的小鼠存活率降低，骨髓细胞数量严重减少，出现红系贫血和B细胞淋巴细胞减少。这些表型与干细胞和祖细胞的分化偏差以及HSC池扩大有关。从机制上讲，Atad3a与线粒体通道成分Tom40和Tim23相互作用，并作为一个桥梁因子来促进线粒体自噬蛋白Pink1的适当运输和加工。Atad3a的缺失导致Pink1积累并激活线粒体自噬。值得注意的是，在Atad3a缺陷小鼠中删除Pink1显著“挽救”了线粒体自噬缺陷，从而导致祖细胞和HSC池的恢复。我们的数据表明，Atad3a抑制Pink1依赖性线粒体自噬，从而在造血稳态中起关键作用。
