Mochizuki-Kashio Makiko, Otsuki Noriko, Fujiki Kota, Abdelhamd Sherif, Kurre Peter, Grompe Markus, Iwama Atsushi, Saito Kayoko, Nakamura-Ishizu Ayako
Department of Mieroscopic and Developmental Anatomy, Tokyo Women's Medical University, Tokyo, Japan.
Institute of Medical Genetics, Tokyo Women's Medical University, Tokyo, Japan.
Front Oncol. 2023 Mar 7;13:1108430. doi: 10.3389/fonc.2023.1108430. eCollection 2023.
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.
范可尼贫血（FA）是一种遗传性骨髓（BM）衰竭疾病，通常在学龄期被诊断出来。然而，在小鼠模型中，FA基因功能的破坏会导致胎儿肝脏造血干细胞（FL HSC）数量在更早的时候下降，这与复制应激（RS）增加有关。最近的报道表明，线粒体代谢和清除对于长期BM HSC功能至关重要。有趣的是，已有报道称FA细胞中的线粒体自噬受损。我们假设FL HSC中的RS会影响线粒体代谢，以研究胎儿FA的病理生理学。结果表明，在成年小鼠BM HSC中实验性诱导的RS会引起线粒体代谢和线粒体自噬的显著增加。反映FA发育过程中的生理RS，在FANCD2缺陷的FL HSC中观察到线粒体代谢和线粒体自噬增加，而成年FANCD2缺陷小鼠的BM HSC中线粒体自噬则显著减少。这些数据表明，RS激活了HSC中的线粒体代谢和线粒体自噬。
