Ma Liyun, Hui Jialiang, He Guangting, Qin Zaisheng
Department of Anesthesiology, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, Guangdong, China; Guangdong Provincial Key Laboratory of Precision Anesthesia and Perioperative Organ Protection, 510515, Guangzhou, Guangdong, China.
Department of Transplantation, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, China.
Exp Cell Res. 2025 Jul 15;450(2):114682. doi: 10.1016/j.yexcr.2025.114682. Epub 2025 Jul 21.
Acute kidney injury (AKI) is a severe clinical syndrome that critically threatens patients' lives and health. It is characterized by complex pathogenesis and lacks effective therapeutic strategies. Mitochondrial homeostasis disruption plays a pivotal role in AKI progression, yet its precise molecular mechanisms remain unclear. This study aimed to investigate the role of DNAJC6 in AKI and its molecular mechanism of mitochondrial homeostasis regulation.
Utilizing cisplatin-induced mouse AKI models and human proximal tubular epithelial cell line HK-2, we employed multiple experimental approaches including bioinformatics analysis, cell transfection, immunohistochemical staining, immunofluorescence, TUNEL assay, and mitochondrial function detection to explore the role and molecular mechanisms of DNAJC6 in AKI.
In cisplatin-induced AKI models, renal DNAJC6 expression decreased. DNAJC6 overexpression markedly alleviated kidney injury, reduced cell apoptosis, and attenuated inflammatory responses. Mechanistic investigations revealed that DNAJC6 regulated mitochondrial homeostasis by promoting PGC-1α nuclear translocation. Specifically, DNAJC6 improved mitochondrial respiratory function and reduced mitochondrial oxidative stress levels. Moreover, DNAJC6 enhanced mitochondrial biogenesis and suppressed inflammatory factor expression. Upon PGC-1α knockdown, DNAJC6's protective effects were almost completely abolished, confirming that PGC-1α was a critical molecular mediator.
This study elucidated the molecular mechanism by which DNAJC6 protected renal tubular epithelial cells through PGC-1α-mediated mitochondrial homeostasis in AKI. These findings not only provide a novel perspective on AKI pathogenesis but also offer a crucial theoretical foundation for developing potential therapeutic strategies. DNAJC6 emerges as a promising molecular target for AKI treatment.
急性肾损伤（AKI）是一种严重的临床综合征，严重威胁患者的生命和健康。其发病机制复杂，缺乏有效的治疗策略。线粒体稳态破坏在AKI进展中起关键作用，但其确切分子机制仍不清楚。本研究旨在探讨DNAJC6在AKI中的作用及其调节线粒体稳态的分子机制。
利用顺铂诱导的小鼠AKI模型和人近端肾小管上皮细胞系HK-2，我们采用了多种实验方法，包括生物信息学分析、细胞转染、免疫组织化学染色、免疫荧光、TUNEL检测和线粒体功能检测，以探讨DNAJC6在AKI中的作用和分子机制。
在顺铂诱导的AKI模型中，肾脏DNAJC6表达降低。DNAJC6过表达显著减轻肾脏损伤，减少细胞凋亡，并减轻炎症反应。机制研究表明，DNAJC6通过促进PGC-1α核转位来调节线粒体稳态。具体而言，DNAJC6改善线粒体呼吸功能，降低线粒体氧化应激水平。此外，DNAJC6增强线粒体生物合成并抑制炎症因子表达。在敲低PGC-1α后，DNAJC6的保护作用几乎完全消失，证实PGC-1α是关键的分子介质。
本研究阐明了DNAJC6在AKI中通过PGC-1α介导的线粒体稳态保护肾小管上皮细胞的分子机制。这些发现不仅为AKI发病机制提供了新的视角，也为开发潜在治疗策略提供了重要的理论基础。DNAJC6成为AKI治疗的一个有前景的分子靶点。
