A New Protein Regulating Mitochondrial Function for Maintaining Hematopoietic Stem Cell Viability: The Role of Nynrin

Biochemistry Hematology Life Sciences Immunology Medicine Cell Biology
Hematopoietic Stem Cells Mitochondrial Function Nynrin Radiation Tolerance Cell Cycle

The Role of Nynrin: A New Protein that Regulates Mitochondrial Function to Maintain Hematopoietic Stem Cell Activity

Nynrin Protects Hematopoietic Stem Cell Function by Inhibiting Mitochondrial Permeability Transition Pore Opening

Background and Research Motivation

Hematopoietic stem cells (HSCs) are core cells that maintain the function of the hematopoietic system, showing unique adaptability to stress environments such as radiation damage. However, while conventional radiotherapy (RT) is widely used in the treatment of diseases like cervical cancer and rectal cancer, its radiation damage to HSCs in the bone marrow may cause severe hematopoietic toxicity, including bone marrow failure and cytopenia. Extensive research indicates that RT can significantly reduce the homeostasis of HSCs, affecting their long-term proliferation and self-renewal capabilities. Recently, mitochondria have been identified as key regulators of HSC homeostasis, but the specific molecular mechanisms remain unclear. In this study, Zhou et al. focused on the transcription factor Nynrin to explore its role in HSC homeostasis and stress response, revealing its function in protecting HSCs by regulating mitochondrial function and inhibiting the opening of permeability transition pores (MPTP).

Research Source

This research was conducted by Chengfang Zhou, Mei Kuang, and others, involving institutions such as Chongqing Medical University and the Third Military Medical University (Army Medical University). The paper was published on September 5, 2024, in “Cell Stem Cell.”

Research Process

The study mainly involved constructing knockout and overexpression mouse models of the Nynrin gene, combined with cell experiments, gene expression analysis, and related molecular mechanism research to systematically analyze the role of Nynrin in hematopoietic stem cells. The main experimental steps are as follows:

  1. Establishment of Nynrin Gene Knockout and Overexpression Models
    Using Nynrin knockout models (Nynrin-cko) and overexpression models (Nynrin-tg), the study explored the impact of this gene on HSCs under normal and radioactive stress environments. A conditional knockout model (Nynrin^fl/flTie2-Cre) was also developed to specifically delete Nynrin in the hematopoietic system.

  2. Radiation Stress Experiments
    In hematopoietic stem and progenitor cells (HSPCs), radiation treatment was conducted with doses ranging from 0.5 to 4Gy to study the direct impact of radiation on HSCs, analyzing changes in indicators such as mitochondrial membrane potential (MMP), reactive oxygen species (ROS) levels, and MPTP opening.

  3. Gene Expression and Protein Detection
    Using techniques like single-cell RNA sequencing, RNA sequencing, and immunoprecipitation, the distribution of Nynrin expression in HSCs and its role in MPTP regulation were analyzed. The study also evaluated its relationship with the ppif gene, finding that Nynrin maintains HSC function by inhibiting the expression of ppif, which encodes the Cyclophilin D gene.

  4. Competitive Bone Marrow Transplantation (CBMT) and Long-term Transplantation Experiments
    To assess the impact of Nynrin on the regeneration and self-renewal capabilities of HSCs, multiple rounds of transplantation experiments were conducted to observe the effects of Nynrin knockout and overexpression on HSC proliferation, survival, and bone marrow reconstruction efficiency.

  5. Interference and Pharmacological Experiments
    Through the combined use of Cyclosporin A (CSA) and N-acetyl-L-cysteine (NAC), the study investigated the restorative effects of exogenously inhibiting MPTP opening and ROS levels on the function of HSCs in Nynrin knockout mice.

Main Research Findings

  1. High Expression of Nynrin in HSCs
    The experiments found that under both homeostatic and stress conditions, Nynrin is significantly more expressed in HSCs than in other blood cells. After Nynrin gene knockout, the frequency of HSCs decreases, proliferation increases, and self-renewal capability is impaired, indicating the importance of Nynrin in HSC homeostasis.

  2. Nynrin Inhibits MPTP Opening and Controls ROS Levels
    Nynrin gene knockout leads to excessive opening of the mitochondrial permeability transition pore (MPTP), elevated ROS levels, and reduced mitochondrial membrane potential, triggering cell necrosis and apoptosis-like phenotypes. By inhibiting the expression of Cyclophilin D, a component of MPTP, Nynrin significantly reduces the severity of radiation damage.

  3. Nynrin Knockout Significantly Increases Radiosensitivity
    Nynrin knockout mice showed significantly shortened survival times after receiving a 7Gy dose of whole-body irradiation, with slower HSC proliferation and apoptotic characteristics. In contrast, Nynrin overexpression markedly improved the radiotolerance of HSCs, maintaining cell survival.

  4. The Impact of Nynrin on HSC Proliferation and Self-renewal
    HSCs lacking Nynrin exhibited lower proliferation activity in vitro and displayed progressively declining engraftment success rates in multiple bone marrow transplantation experiments. Furthermore, the haploinsufficiency of the ppif gene (ppif+/−) significantly restored the function of Nynrin knockout HSCs.

Research Conclusions and Value

This study reveals the critical role of Nynrin in HSC homeostasis and response to radiation damage. Nynrin protects cell survival and function by downregulating ppif expression to inhibit MPTP opening, avoiding excessive ROS accumulation. Additionally, the overexpression of Nynrin can serve as a potential radioprotective strategy to enhance HSC survival during radiotherapy. The study also found that Nynrin is upregulated in acute myeloid leukemia (AML), suggesting its potential protective role in cancer stem cells.

Research Highlights

  1. Revealing the Core Regulatory Role of Nynrin in HSC Mitochondrial Homeostasis
    Through the construction of various experimental models, the study demonstrated that Nynrin counteracts radiation and oxidative stress in HSCs by inhibiting MPTP opening and regulating ROS levels, maintaining cell function.

  2. Discovering the Potential Application of Nynrin in Radiotherapy
    By overexpressing the Nynrin gene, the radiotolerance of HSCs was significantly improved, providing new insights for protecting HSCs during cancer radiotherapy.

  3. Compensatory Role of ppif Gene Haploinsufficiency
    In Nynrin-deficient mice, the study restored part of the HSC function through ppif gene haploinsufficiency or external drug intervention, supporting the development of Nynrin-related protective therapeutic measures in the future.

Additional Information and Future Prospects

Despite the substantial evidence provided by this study on the role of Nynrin in HSCs, there are still some limitations. Firstly, the research is primarily based on mouse models, and future verification in human samples is needed; secondly, the dual role of Nynrin in protecting normal HSCs and promoting AML cell proliferation indicates potential challenges in therapeutic applications. How to selectively inhibit its oncogenic functions while preserving its protective role during treatment will become the focus of subsequent research.