Document Type
Article
Publication Date
2019
College/Unit
School of Pharmacy
Department/Program/Center
Pharmaceutical Sciences
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.
Digital Commons Citation
Chatla, Srinivas; Du, Wei; Wilson, Andrew F.; Meetei, Amom Ruhikanta; and Pang, Qishen, "Fancd2-deficient Hematopoietic Stem and Progenitor Cells Depend on Augmented Mitochondrial Translation for Survival and Proliferation" (2019). Faculty & Staff Scholarship. 1695.
https://researchrepository.wvu.edu/faculty_publications/1695
Source Citation
Chatla, S., Du, W., Wilson, A. F., Meetei, A. R., & Pang, Q. (2019). Fancd2-deficient hematopoietic stem and progenitor cells depend on augmented mitochondrial translation for survival and proliferation. Stem Cell Research, 40, 101550. https://doi.org/10.1016/j.scr.2019.101550
Comments
© 2019 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/).T