Replication stress increases mitochondrial metabolism and mitophagy in FANCD2 deficient fetal liver hematopoietic stem cells

Makiko Mochizuki-Kashio; Noriko Otsuki; Kota Fujiki; Sherif Abdelhamd; Peter Kurre; Markus Grompe; Atsushi Iwama; Kayoko Saito; Ayako Nakamura-Ishizu

doi:10.3389/fonc.2023.1108430

Replication stress increases mitochondrial metabolism and mitophagy in FANCD2 deficient fetal liver hematopoietic stem cells

Front Oncol. 2023 Mar 7:13:1108430. doi: 10.3389/fonc.2023.1108430. eCollection 2023.

Authors

Makiko Mochizuki-Kashio¹, Noriko Otsuki², Kota Fujiki³, Sherif Abdelhamd⁴, Peter Kurre⁵, Markus Grompe⁶, Atsushi Iwama⁷, Kayoko Saito², Ayako Nakamura-Ishizu¹

Affiliations

¹ Department of Mieroscopic and Developmental Anatomy, Tokyo Women's Medical University, Tokyo, Japan.
² Institute of Medical Genetics, Tokyo Women's Medical University, Tokyo, Japan.
³ Department of Hygiene and Fublic Health, Tokyo Women's Medical University, Tokyo, Japan.
⁴ Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, United States.
⁵ Children's Hospital of Philadelphia, Comprehensive Bone Marrow Failure Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States.
⁶ Papé Family Pediatric Research Institute, Oregon Stem Cell Center, Oregon Health & Science University, Portland, OR, United States.
⁷ Division of Stem Cell and Molecular Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.

Abstract

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.

Keywords: FANCD2; Hematopoietic stem cell; fetal liver; mitochondria metabolism; mitophagy; replication stress.

Grants and funding

This work was supported by JSPS KAKENHI Grant Number JP21K08425: Funds for the Development of Human Resources in Science and Technology: Initiative for Realizing Diversity in the Research Environment: Grant from International Joint Usage/Research Center, the Institute of Medical Science, the University of Tokyo.