Atad3a suppresses Pink1-dependent mitophagy to maintain homeostasis of hematopoietic progenitor cells article

Guoxiang Jin, Chuan Xu, Xian Zhang, Jie Long, Abdol Hossein Rezaeian, Chunfang Liu, Mark E. Furth, Steven Kridel, Boris Pasche, Xiu Wu Bian, Hui Kuan Lin

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24 Scopus citations

Abstract

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. The survival of hematopoietic stem cells requires tight regulation of mitophagy. Lin and colleagues show that Atad3a regulates mitophagy in these cells by sequestering the mitophagy initiator Pink1 and directing its import via the mitochondrial Tom40-Tim23 complex.

Original languageEnglish (US)
Pages (from-to)29-40
Number of pages12
JournalNature Immunology
Volume19
Issue number1
DOIs
StatePublished - Jan 1 2018

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Jin, G., Xu, C., Zhang, X., Long, J., Rezaeian, A. H., Liu, C., Furth, M. E., Kridel, S., Pasche, B., Bian, X. W., & Lin, H. K. (2018). Atad3a suppresses Pink1-dependent mitophagy to maintain homeostasis of hematopoietic progenitor cells article. Nature Immunology, 19(1), 29-40. https://doi.org/10.1038/s41590-017-0002-1