线粒体是造血干细胞 (HSC) 稳态的关键调节因子。我们的研究确定转录因子 Nynrin 通过调节线粒体功能而成为 HSC 维持的关键调节因子。在稳态和应激条件下，Nynrin 在 HSC 中高度表达。敲除 Nynrin 会降低 HSC 频率、休眠和自我更新，并增加线粒体功能障碍，表现为 mPTP 开放异常、线粒体肿胀和 ROS 水平升高。这些变化降低了 HSC 的辐射耐受性并促进坏死样表型。相比之下，HSC 中 Nynrin 的过度表达可减少辐射 (IR) 诱导的致死率。 Nynrin 的缺失会激活 Ppif，导致亲环蛋白 D (CypD) 过度表达并进一步导致线粒体功能障碍。 Ppif 单倍体不足或 CypD 药理抑制等策略可显着减轻这些影响，恢复 Nynrin 缺陷小鼠的 HSC 功能。这项研究确定 Nynrin 是 HSC 中线粒体功能的关键调节因子，强调了在癌症治疗期间保持干细胞活力的潜在治疗靶点。版权所有 © 2024 作者。由爱思唯尔公司出版。保留所有权利。

Mitochondria are key regulators of hematopoietic stem cell (HSC) homeostasis. Our research identifies the transcription factor Nynrin as a crucial regulator of HSC maintenance by modulating mitochondrial function. Nynrin is highly expressed in HSCs under both steady-state and stress conditions. The knockout Nynrin diminishes HSC frequency, dormancy, and self-renewal, with increased mitochondrial dysfunction indicated by abnormal mPTP opening, mitochondrial swelling, and elevated ROS levels. These changes reduce HSC radiation tolerance and promote necrosis-like phenotypes. By contrast, Nynrin overexpression in HSCs diminishes irradiation (IR)-induced lethality. The deletion of Nynrin activates Ppif, leading to overexpression of cyclophilin D (CypD) and further mitochondrial dysfunction. Strategies such as Ppif haploinsufficiency or pharmacological inhibition of CypD significantly mitigate these effects, restoring HSC function in Nynrin-deficient mice. This study identifies Nynrin as a critical regulator of mitochondrial function in HSCs, highlighting potential therapeutic targets for preserving stem cell viability during cancer treatment.Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.