日本东京国立全球健康与医学中心研究所Keiyo Takubo课题组近日取得一项新成果。经过不懈努力，他们的最新研究探明了SDHAF1通过促进线粒体ATP的产生，赋予衰老造血干细胞代谢恢复能力。该项研究成果发表在2024年5月20日出版的《细胞—干细胞》上。

该团队报道造血干细胞(HSC)获得促进细胞存活的代谢恢复能力。高分辨率实时ATP分析与葡萄糖追踪和代谢通量分析显示，衰老的造血干细胞重编程其代谢以激活戊糖磷酸途径(PPP)，在稳定状态下变得更耐氧化应激，更少依赖于糖酵解ATP的产生。

因此，年老的造血干细胞可以在没有糖酵解的情况下存活，适应骨髓中的生理细胞因子环境。在机制上，年老的造血干细胞在应激过程中增强线粒体复合物II代谢，促进ATP的产生。

此外，由于生长期低浓度的血小板生成素(TPO)暴露，老龄造血干细胞中琥珀酸脱氢组装因子1 (SDHAF1)增加，使线粒体在代谢应激时能够快速产生ATP，从而提高生存率。这项研究为老年造血干细胞通过代谢重编程获得恢复能力，及其改善与年龄相关的造血异常的分子基础提供了见解。

附：英文原文

Title: SDHAF1 confers metabolic resilience to aging hematopoietic stem cells by promoting mitochondrial ATP production

Author: 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, Kazuya Shimoda, Makoto Suematsu, Toshio Suda, Keiyo Takubo

Issue&Volume: 2024-05-20

Abstract: Aging generally predisposes stem cells to functional decline, impairing tissue homeostasis.Here, we report that hematopoietic stem cells (HSCs) acquire metabolic resiliencethat promotes cell survival. High-resolution real-time ATP analysis with glucose tracingand metabolic flux analysis revealed that old HSCs reprogram their metabolism to activatethe pentose phosphate pathway (PPP), becoming more resistant to oxidative stress andless dependent on glycolytic ATP production at steady state. As a result, old HSCscan survive without glycolysis, adapting to the physiological cytokine environmentin bone marrow. Mechanistically, old HSCs enhance mitochondrial complex II metabolismduring stress to promote ATP production. Furthermore, increased succinate dehydrogenaseassembly factor 1 (SDHAF1) in old HSCs, induced by physiological low-concentrationthrombopoietin (TPO) exposure, enables rapid mitochondrial ATP production upon metabolicstress, thereby improving survival. This study provides insight into the acquisitionof resilience through metabolic reprogramming in old HSCs and its molecular basisto ameliorate age-related hematopoietic abnormalities.

DOI: 10.1016/j.stem.2024.04.023

Source: https://www.cell.com/cell-stem-cell/abstract/S1934-5909(24)00176-0