Nynrin preserves hematopoietic stem cell function by inhibiting the mitochondrial permeability transition pore opening,Cell Stem Cell

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Nynrin preserves hematopoietic stem cell function by inhibiting the mitochondrial permeability transition pore opening
Cell Stem Cell ( IF 19.8 ) Pub Date : 2024-07-01 , DOI: 10.1016/j.stem.2024.06.007
Chengfang Zhou ₁ , Mei Kuang ₂ , Yin Tao ₃ , Jianming Wang ₁ , Yu Luo ₁ , Yinghao Fu ₁ , Zhe Chen ₁ , Yuanyuan Liu ₁ , Zhigang Li ₁ , Weiru Wu ₁ , Li Wang ₄ , Ying Dou ₅ , Junping Wang ₆ , Yu Hou ₇

Affiliation

Department of Radiological Medicine, School of Basic Medical Sciences, Chongqing Medical University, Chongqing 400016, China.
Department of Hematology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China.
Department of Gynecology, The affiliated ZhuZhou Hospital (ZhuZhou Central Hospital), Xiangya Medical College of Central South University, Zhuzhou, Hunan 412007, China.
Department of Hematology, The First Affiliated Hospital of Chongqing Medical University, 1 Youyi Road, Yuzhong Qu, Chongqing 400016, China.
Department of Hematology, Children's Hospital of Chongqing Medical University, Chongqing 400014, China.
State Key Laboratory of Trauma and Chemical Poisoning, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing 400038, China.
Department of Radiological Medicine, School of Basic Medical Sciences, Chongqing Medical University, Chongqing 400016, China; Department of Hematology, Children's Hospital of Chongqing Medical University, Chongqing 400014, China; Chongqing Key Laboratory of Hematology and Microenvironment, Chongqing Medical University, Chongqing 400016, China.

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.

中文翻译：

Nynrin 通过抑制线粒体通透性转换孔开放来保护造血干细胞功能

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 的药物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 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。

更新日期：2024-07-01

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