机构：[1]Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China[2]Department of CancerBiology, Wake Forest School of Medicine, Winston-Salem, NC, USA[3]Department of Molecular and Cellular Oncology, The University of Texas MDAnderson Cancer Center, Houston, TX, USA[4]Department of Oncology, Chengdu Military General Hospital, Chengdu, Sichuan, China[5]Department ofPathology School of Basic Medical Science, Guangzhou Medical University, Guangzhou, Guangdong, China[6]Wake Forest Innovations, Wake Forest BaptistMedical Center, Winston-Salem, NC, USA[7]Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan[8]Department ofBiotechnology, Asia University, Taichung, Taiwan
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.
基金：
Supported by the
National Key Research and Development Program of China (2016YFA0101200 to
X.-W.B.), the National Natural Science Foundation of China (61327902-04 to X.-W.B.),
the US National Institutes of Health (R01 CA182424 and R01 CA193813 to H.-K.L.) and
Wake Forest University School of Medicine (start-up funds to H.-K.L.).
第一作者机构：[1]Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China[2]Department of CancerBiology, Wake Forest School of Medicine, Winston-Salem, NC, USA[3]Department of Molecular and Cellular Oncology, The University of Texas MDAnderson Cancer Center, Houston, TX, USA
共同第一作者：
通讯作者：
通讯机构：[2]Department of CancerBiology, Wake Forest School of Medicine, Winston-Salem, NC, USA[3]Department of Molecular and Cellular Oncology, The University of Texas MDAnderson Cancer Center, Houston, TX, USA[7]Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan[8]Department ofBiotechnology, Asia University, Taichung, Taiwan
推荐引用方式(GB/T 7714)：
Jin Guoxiang,Xu Chuan,Zhang Xian,et al.Atad3a suppresses Pink1-dependent mitophagy to maintain homeostasis of hematopoietic progenitor cells.[J].Nature immunology.2018,19(1):29-+.doi:10.1038/s41590-017-0002-1.
APA：
Jin Guoxiang,Xu Chuan,Zhang Xian,Long Jie,Rezaeian Abdol Hossein...&Lin Hui-Kuan.(2018).Atad3a suppresses Pink1-dependent mitophagy to maintain homeostasis of hematopoietic progenitor cells..Nature immunology,19,(1)
MLA：
Jin Guoxiang,et al."Atad3a suppresses Pink1-dependent mitophagy to maintain homeostasis of hematopoietic progenitor cells.".Nature immunology 19..1(2018):29-+
医学