Department of Nutritional Sciences and Toxicology, University of California, Berkeley, CA, USA.
Metabolic Biology Graduate Program, University of California, Berkeley, CA, USA.
Nat Aging. 2024 Oct;4(10):1384-1393. doi: 10.1038/s43587-024-00670-8. Epub 2024 Jul 23.
How hematopoietic stem cells (HSCs) maintain metabolic homeostasis to support tissue repair and regeneration throughout the lifespan is elusive. Here, we show that CD38, an NAD-dependent metabolic enzyme, promotes HSC proliferation by inducing mitochondrial Ca influx and mitochondrial metabolism in young mice. Conversely, aberrant CD38 upregulation during aging is a driver of HSC deterioration in aged mice due to dysregulated NAD metabolism and compromised mitochondrial stress management. The mitochondrial calcium uniporter, a mediator of mitochondrial Ca influx, also supports HSC proliferation in young mice yet drives HSC decline in aged mice. Pharmacological inactivation of CD38 reverses HSC aging and the pathophysiological changes of the aging hematopoietic system in aged mice. Together, our study highlights an NAD metabolic checkpoint that balances mitochondrial activation to support HSC proliferation and mitochondrial stress management to enhance HSC self-renewal throughout the lifespan, and links aberrant Ca signaling to HSC aging.
造血干细胞（HSCs）如何维持代谢稳态以支持整个生命周期中的组织修复和再生仍然难以捉摸。在这里，我们表明，NAD 依赖性代谢酶 CD38 通过诱导年轻小鼠中线粒体 Ca 内流和线粒体代谢来促进 HSC 增殖。相反，衰老过程中异常的 CD38 上调是由于 NAD 代谢失调和线粒体应激管理受损导致老年小鼠 HSC 恶化的驱动因素。线粒体钙单向转运体是线粒体 Ca 内流的介质，它也支持年轻小鼠中的 HSC 增殖，但在老年小鼠中却导致 HSC 下降。CD38 的药理学失活可逆转老年小鼠的 HSC 衰老和衰老造血系统的病理生理变化。总之，我们的研究强调了一个 NAD 代谢检查点，该检查点平衡线粒体的激活以支持 HSC 增殖，并平衡线粒体应激管理以增强整个生命周期中的 HSC 自我更新，将异常的 Ca 信号与 HSC 衰老联系起来。
