TY - JOUR
T1 - Replication stress increases mitochondrial metabolism and mitophagy in FANCD2 deficient fetal liver hematopoietic stem cells
AU - Mochizuki-Kashio, Makiko
AU - Otsuki, Noriko
AU - Fujiki, Kota
AU - Abdelhamd, Sherif
AU - Kurre, Peter
AU - Grompe, Markus
AU - Iwama, Atsushi
AU - Saito, Kayoko
AU - Nakamura-Ishizu, Ayako
N1 - Publisher Copyright:
Copyright © 2023 Mochizuki-Kashio, Otsuki, Fujiki, Abdelhamd, Kurre, Grompe, Iwama, Saito and Nakamura-Ishizu.
PY - 2023
Y1 - 2023
N2 - Fanconi Anemia (FA) is an inherited bone marrow (BM) failure disorder commonly diagnosed during school age. However, in murine models, disrupted function of FA genes leads to a much earlier decline in fetal liver hematopoietic stem cell (FL HSC) number that is associated with increased replication stress (RS). Recent reports have shown mitochondrial metabolism and clearance are essential for long-term BM HSC function. Intriguingly, impaired mitophagy has been reported in FA cells. We hypothesized that RS in FL HSC impacts mitochondrial metabolism to investigate fetal FA pathophysiology. Results show that experimentally induced RS in adult murine BM HSCs evoked a significant increase in mitochondrial metabolism and mitophagy. Reflecting the physiological RS during development in FA, increase mitochondria metabolism and mitophagy were observed in FANCD2-deficient FL HSCs, whereas BM HSCs from adult FANCD2-deficient mice exhibited a significant decrease in mitophagy. These data suggest that RS activates mitochondrial metabolism and mitophagy in HSC.
AB - Fanconi Anemia (FA) is an inherited bone marrow (BM) failure disorder commonly diagnosed during school age. However, in murine models, disrupted function of FA genes leads to a much earlier decline in fetal liver hematopoietic stem cell (FL HSC) number that is associated with increased replication stress (RS). Recent reports have shown mitochondrial metabolism and clearance are essential for long-term BM HSC function. Intriguingly, impaired mitophagy has been reported in FA cells. We hypothesized that RS in FL HSC impacts mitochondrial metabolism to investigate fetal FA pathophysiology. Results show that experimentally induced RS in adult murine BM HSCs evoked a significant increase in mitochondrial metabolism and mitophagy. Reflecting the physiological RS during development in FA, increase mitochondria metabolism and mitophagy were observed in FANCD2-deficient FL HSCs, whereas BM HSCs from adult FANCD2-deficient mice exhibited a significant decrease in mitophagy. These data suggest that RS activates mitochondrial metabolism and mitophagy in HSC.
KW - FANCD2
KW - Hematopoietic stem cell
KW - fetal liver
KW - mitochondria metabolism
KW - mitophagy
KW - replication stress
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U2 - 10.3389/fonc.2023.1108430
DO - 10.3389/fonc.2023.1108430
M3 - Article
AN - SCOPUS:85152091867
SN - 2234-943X
VL - 13
JO - Frontiers in Oncology
JF - Frontiers in Oncology
M1 - 1108430
ER -