SDHAF1通过促进线粒体ATP的产生,赋予衰老造血干细胞新陈代谢的恢复能力

IF 19.8 1区 医学 Q1 CELL & TISSUE ENGINEERING Cell stem cell Pub Date : 2024-05-20 DOI:10.1016/j.stem.2024.04.023
Shintaro Watanuki, Hiroshi Kobayashi, Yuki Sugiura, Masamichi Yamamoto, Daiki Karigane, Kohei Shiroshita, Yuriko Sorimachi, Takayuki Morikawa, Shinya Fujita, Kotaro Shide, Miho Haraguchi, Shinpei Tamaki, Takumi Mikawa, Hiroshi Kondoh, Hiroyasu Nakano, Kenta Sumiyama, Go Nagamatsu, Nobuhito Goda, Shinichiro Okamoto, Ayako Nakamura-Ishizu, Keiyo Takubo
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引用次数: 0

摘要

衰老通常会导致干细胞功能衰退,损害组织稳态。在这里,我们报告了造血干细胞(HSCs)获得了促进细胞存活的代谢恢复能力。通过葡萄糖追踪和代谢通量分析进行的高分辨率实时ATP分析表明,老年造血干细胞重塑了新陈代谢,激活了磷酸戊糖途径(PPP),变得更能抵抗氧化应激,在稳态时对糖酵解ATP生成的依赖性降低。因此,老年造血干细胞可以在没有糖酵解的情况下存活,从而适应骨髓中的细胞因子生理环境。从机制上讲,老年造血干细胞在应激时会增强线粒体复合体 II 的代谢,以促进 ATP 的产生。此外,在生理性低浓度血小板生成素(TPO)暴露的诱导下,老年造血干细胞中琥珀酸脱氢酶组装因子1(SDHAF1)的增加可使线粒体在代谢应激时快速产生ATP,从而提高存活率。这项研究深入探讨了老年造血干细胞通过代谢重编程获得复原力的过程及其分子基础,从而改善与年龄相关的造血异常。
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SDHAF1 confers metabolic resilience to aging hematopoietic stem cells by promoting mitochondrial ATP production

Aging generally predisposes stem cells to functional decline, impairing tissue homeostasis. Here, we report that hematopoietic stem cells (HSCs) acquire metabolic resilience that promotes cell survival. High-resolution real-time ATP analysis with glucose tracing and metabolic flux analysis revealed that old HSCs reprogram their metabolism to activate the pentose phosphate pathway (PPP), becoming more resistant to oxidative stress and less dependent on glycolytic ATP production at steady state. As a result, old HSCs can survive without glycolysis, adapting to the physiological cytokine environment in bone marrow. Mechanistically, old HSCs enhance mitochondrial complex II metabolism during stress to promote ATP production. Furthermore, increased succinate dehydrogenase assembly factor 1 (SDHAF1) in old HSCs, induced by physiological low-concentration thrombopoietin (TPO) exposure, enables rapid mitochondrial ATP production upon metabolic stress, thereby improving survival. This study provides insight into the acquisition of resilience through metabolic reprogramming in old HSCs and its molecular basis to ameliorate age-related hematopoietic abnormalities.

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来源期刊
Cell stem cell
Cell stem cell 生物-细胞生物学
CiteScore
37.10
自引率
2.50%
发文量
151
审稿时长
42 days
期刊介绍: Cell Stem Cell is a comprehensive journal covering the entire spectrum of stem cell biology. It encompasses various topics, including embryonic stem cells, pluripotency, germline stem cells, tissue-specific stem cells, differentiation, epigenetics, genomics, cancer stem cells, stem cell niches, disease models, nuclear transfer technology, bioengineering, drug discovery, in vivo imaging, therapeutic applications, regenerative medicine, clinical insights, research policies, ethical considerations, and technical innovations. The journal welcomes studies from any model system providing insights into stem cell biology, with a focus on human stem cells. It publishes research reports of significant importance, along with review and analysis articles covering diverse aspects of stem cell research.
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