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Stem Cell Res. 2019 Oct;40:101550. doi: 10.1016/j.scr.2019.101550. Epub 2019 Aug 23.

Fancd2-deficient hematopoietic stem and progenitor cells depend on augmented mitochondrial translation for survival and proliferation.

Author information

1
Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, United States of America. Electronic address: Srinivas.Chatla@cchmc.org.
2
Department of Pharmaceutical Sciences, School of Pharmacy, West Virginia University, Morgantown, WV 26506, United States of America. Electronic address: wei.du@hsc.wvu.edu.
3
Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, United States of America. Electronic address: Andrew.Wilson@cchmc.org.
4
Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, United States of America; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, United States of America. Electronic address: Ruhikanta.Meetei@cchmc.org.
5
Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, United States of America; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, United States of America. Electronic address: Qishen.Pang@cchmc.org.

Abstract

Members of the Fanconi anemia (FA) protein family are involved in multiple cellular processes including response to DNA damage and oxidative stress. Here we show that a major FA protein, Fancd2, plays a role in mitochondrial biosynthesis through regulation of mitochondrial translation. Fancd2 interacts with Atad3 and Tufm, which are among the most frequently identified components of the mitochondrial nucleoid complex essential for mitochondrion biosynthesis. Deletion of Fancd2 in mouse hematopoietic stem and progenitor cells (HSPCs) leads to increase in mitochondrial number, and enzyme activity of mitochondrion-encoded respiratory complexes. Fancd2 deficiency increases mitochondrial protein synthesis and induces mitonuclear protein imbalance. Furthermore, Fancd2-deficient HSPCs show increased mitochondrial respiration and mitochondrial reactive oxygen species. By using a cell-free assay with mitochondria isolated from WT and Fancd2-KO HSPCs, we demonstrate that the increased mitochondrial protein synthesis observed in Fancd2-KO HSPCs was directly linked to augmented mitochondrial translation. Finally, Fancd2-deficient HSPCs are selectively sensitive to mitochondrial translation inhibition and depend on augmented mitochondrial translation for survival and proliferation. Collectively, these results suggest that Fancd2 restricts mitochondrial activity through regulation of mitochondrial translation, and that augmented mitochondrial translation and mitochondrial respiration may contribute to HSC defect and bone marrow failure in FA.

KEYWORDS:

Fanconi anemia; Hematopoietic stem and progenitor cells; Mitochondrial translation; Proliferation; Survival

PMID:
31472450
DOI:
10.1016/j.scr.2019.101550
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