Targeting CB1R Rewires Ca2+-Dependent Mitophagy to Promote Nerve Regeneration.

IF 13.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Theranostics Pub Date : 2025-08-11 eCollection Date: 2025-01-01 DOI:10.7150/thno.119712
Ningning Wang, Weizhen Li, Tuo Yang, Baolong Li, Chuikai Meng, Xiongyao Zhou, Jialu Sun, Kaiming Yu, Shusen Cui, Rangjuan Cao
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引用次数: 0

Abstract

Background: Ion homeostasis is disrupted following nerve injury, and elevated Ca2+ levels have been reported to induce Schwann cell (SC) death. Notably, clinical interventions such as electrical stimulation enhance Ca2+ influx and facilitate nerve regeneration. These findings highlight the need to clarify the precise role of Ca2+ signaling in nerve regeneration. Methods: We assessed extracellular Ca2+ concentrations in both human and murine peripheral nerve tissues after injury. Transcriptomic profiling identified CB1R as a key Ca2+-related gene and in vitro validation was performed with primary cultured SC and nerve explants. A sciatic nerve crush model was established in SC-specific CB1R knockout mice. Mitophagy, cellular metabolic homeostasis, and axonal regeneration were systematically assessed using proteomics, calcium imaging, and in vivo analyses. Additionally, the CB1R antagonist JD5037 was administered in both sciatic and optic nerve injury models to evaluate its translational potential. Results: Peripheral nerve injury (PNI) leads to elevated extracellular Ca2+ levels at the injury site, where a moderate increase (~1.5-fold) favors SC survival. PNI also induces upregulation of CB1R, genetic ablation of CB1R enhances Ca2+ influx, promotes SC survival, and maintains metabolic homeostasis. Mechanistically, CB1R interference upregulates adenine nucleotide translocase 2 (ANT2) expression, promotes mitochondrial permeability transition pore (mPTP) opening and mitochondrial membrane depolarization, thereby activating PINK1/Parkin-mediated mitophagy. This process improves mitochondrial quality and enhances energy metabolic efficiency, ultimately promoting axonal regeneration and functional recovery. Furthermore, systemic administration of the CB1R antagonist JD5037 similarly enhances regeneration of both peripheral and optic nerves in vivo. Conclusion: Moderate extracellular Ca2+ elevation establishes a pro-regenerative microenvironment after nerve injury. Targeting CB1R facilitates Ca2+ influx, enhances mitophagy via the PINK1/Parkin pathway, and promotes nerve regeneration. These findings identify CB1R as a viable therapeutic target and support the translational potential of JD5037 for nerve injury treatment.

靶向CB1R重组Ca2+依赖性有丝分裂促进神经再生。
背景:离子稳态在神经损伤后被破坏,钙离子水平升高可诱导雪旺细胞(SC)死亡。值得注意的是,临床干预如电刺激可增强Ca2+内流并促进神经再生。这些发现强调需要澄清Ca2+信号在神经再生中的确切作用。方法:我们评估了损伤后人类和小鼠周围神经组织的细胞外Ca2+浓度。转录组学分析鉴定CB1R是一个关键的Ca2+相关基因,并在原代培养的SC和神经外植体中进行了体外验证。建立sc特异性CB1R敲除小鼠坐骨神经挤压模型。利用蛋白质组学、钙成像和体内分析系统地评估了线粒体自噬、细胞代谢稳态和轴突再生。此外,CB1R拮抗剂JD5037被应用于坐骨神经和视神经损伤模型,以评估其转化潜力。结果:周围神经损伤(PNI)导致损伤部位细胞外Ca2+水平升高,其中适度增加(约1.5倍)有利于SC存活。PNI还诱导CB1R的上调,CB1R的基因消融增强Ca2+内流,促进SC存活,并维持代谢稳态。机制上,CB1R干扰上调腺嘌呤核苷酸转位酶2 (ANT2)表达,促进线粒体通透性过渡孔(mPTP)开放和线粒体膜去极化,从而激活PINK1/帕金森介导的线粒体自噬。这一过程改善了线粒体质量,提高了能量代谢效率,最终促进轴突再生和功能恢复。此外,全身给药CB1R拮抗剂JD5037同样能促进体内外周神经和视神经的再生。结论:适度的细胞外Ca2+升高建立了神经损伤后促进再生的微环境。靶向CB1R促进Ca2+内流,通过PINK1/Parkin途径增强线粒体自噬,促进神经再生。这些发现确定CB1R是一个可行的治疗靶点,并支持JD5037在神经损伤治疗中的转化潜力。
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来源期刊
Theranostics
Theranostics MEDICINE, RESEARCH & EXPERIMENTAL-
CiteScore
25.40
自引率
1.60%
发文量
433
审稿时长
1 months
期刊介绍: Theranostics serves as a pivotal platform for the exchange of clinical and scientific insights within the diagnostic and therapeutic molecular and nanomedicine community, along with allied professions engaged in integrating molecular imaging and therapy. As a multidisciplinary journal, Theranostics showcases innovative research articles spanning fields such as in vitro diagnostics and prognostics, in vivo molecular imaging, molecular therapeutics, image-guided therapy, biosensor technology, nanobiosensors, bioelectronics, system biology, translational medicine, point-of-care applications, and personalized medicine. Encouraging a broad spectrum of biomedical research with potential theranostic applications, the journal rigorously peer-reviews primary research, alongside publishing reviews, news, and commentary that aim to bridge the gap between the laboratory, clinic, and biotechnology industries.
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