Replication stress increases mitochondrial metabolism and mitophagy in FANCD2 deficient fetal liver hematopoietic stem cells
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 s...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-03-01
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| Series: | Frontiers in Oncology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2023.1108430/full |
| _version_ | 1797869313125777408 |
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| author | Makiko Mochizuki-Kashio Noriko Otsuki Kota Fujiki Sherif Abdelhamd Peter Kurre Markus Grompe Atsushi Iwama Kayoko Saito Ayako Nakamura-Ishizu |
| author_facet | Makiko Mochizuki-Kashio Noriko Otsuki Kota Fujiki Sherif Abdelhamd Peter Kurre Markus Grompe Atsushi Iwama Kayoko Saito Ayako Nakamura-Ishizu |
| author_sort | Makiko Mochizuki-Kashio |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-10T00:09:34Z |
| format | Article |
| id | doaj.art-1549e69d8d5b4516bf6cdb405a36854c |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-04-10T00:09:34Z |
| publishDate | 2023-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-1549e69d8d5b4516bf6cdb405a36854c2023-03-16T09:51:37ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2023-03-011310.3389/fonc.2023.11084301108430Replication stress increases mitochondrial metabolism and mitophagy in FANCD2 deficient fetal liver hematopoietic stem cellsMakiko Mochizuki-Kashio0Noriko Otsuki1Kota Fujiki2Sherif Abdelhamd3Peter Kurre4Markus Grompe5Atsushi Iwama6Kayoko Saito7Ayako Nakamura-Ishizu8Department of Mieroscopic and Developmental Anatomy, Tokyo Women’s Medical University, Tokyo, JapanInstitute of Medical Genetics, Tokyo Women’s Medical University, Tokyo, JapanDepartment of Hygiene and Fublic Health, Tokyo Women’s Medical University, Tokyo, JapanDepartment of Pathology, St. Jude Children’s Research Hospital, Memphis, TN, United StatesChildren’s Hospital of Philadelphia, Comprehensive Bone Marrow Failure Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United StatesPapé Family Pediatric Research Institute, Oregon Stem Cell Center, Oregon Health & Science University, Portland, OR, United StatesDivision of Stem Cell and Molecular Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, JapanInstitute of Medical Genetics, Tokyo Women’s Medical University, Tokyo, JapanDepartment of Mieroscopic and Developmental Anatomy, Tokyo Women’s Medical University, Tokyo, JapanFanconi 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.https://www.frontiersin.org/articles/10.3389/fonc.2023.1108430/fullHematopoietic stem cellFANCD2replication stressmitochondria metabolismmitophagyfetal liver |
| spellingShingle | Makiko Mochizuki-Kashio Noriko Otsuki Kota Fujiki Sherif Abdelhamd Peter Kurre Markus Grompe Atsushi Iwama Kayoko Saito Ayako Nakamura-Ishizu Replication stress increases mitochondrial metabolism and mitophagy in FANCD2 deficient fetal liver hematopoietic stem cells Frontiers in Oncology Hematopoietic stem cell FANCD2 replication stress mitochondria metabolism mitophagy fetal liver |
| title | Replication stress increases mitochondrial metabolism and mitophagy in FANCD2 deficient fetal liver hematopoietic stem cells |
| title_full | Replication stress increases mitochondrial metabolism and mitophagy in FANCD2 deficient fetal liver hematopoietic stem cells |
| title_fullStr | Replication stress increases mitochondrial metabolism and mitophagy in FANCD2 deficient fetal liver hematopoietic stem cells |
| title_full_unstemmed | Replication stress increases mitochondrial metabolism and mitophagy in FANCD2 deficient fetal liver hematopoietic stem cells |
| title_short | Replication stress increases mitochondrial metabolism and mitophagy in FANCD2 deficient fetal liver hematopoietic stem cells |
| title_sort | replication stress increases mitochondrial metabolism and mitophagy in fancd2 deficient fetal liver hematopoietic stem cells |
| topic | Hematopoietic stem cell FANCD2 replication stress mitochondria metabolism mitophagy fetal liver |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2023.1108430/full |
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