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线粒体转移通过富马酸介导的线粒体自噬激活保护顺铂诱导的听力损失

Mitochondrial transfer protects against cisplatin-induced hearing loss by fumarate-mediated activation of mitophagy.

基础研究耳科IF 8.4Q1

文献信息

中文摘要

背景: 感音神经性听力损失(SNHL)影响全球数百万人,铂类化疗药物已被确定为重要病因。在本研究中,我们阐明了间充质干/基质细胞(MSCs)线粒体转移在小鼠模型中保护顺铂诱导耳蜗损伤的机制。方法:全身给药的MSCs归巢至耳蜗,并通过隧道纳米管将线粒体转移至受损的螺旋神经节神经元(SGNs),导致细胞内三羧酸循环中间产物富马酸水平升高,从而激活线粒体自噬以清除功能障碍的线粒体。结果:在机制上,富马酸二甲酯(DMF)——一种临床可用的富马酸衍生物——共价修饰磷酸酶PPP1CB的第126位半胱氨酸,从而阻断PPP1CB介导的线粒体融合蛋白2(MFN2)去磷酸化,进而增强线粒体自噬并最终保护听觉功能。结论:这些发现揭示,MSCs通过递送健康线粒体并促进受损线粒体清除,在受损SGNs中协调线粒体替换,强调了该策略治疗与线粒体功能障碍相关的SNHL的治疗潜力。

英文摘要

Sensorineural hearing loss (SNHL) affects millions of individuals worldwide, with platinum-based chemotherapeutics identified as a significant cause. In this study, we elucidate the mechanism by which mitochondrial transfer from mesenchymal stem/stromal cells (MSCs) protects against cisplatin-induced cochlear injury in a mouse model. Systemically administered MSCs home to the cochlea and transfer mitochondria to damaged spiral ganglion neurons (SGNs) via tunneling nanotubes, leading to elevated intracellular levels of the Krebs cycle intermediate fumarate, which activates mitophagy to eliminate dysfunctional mitochondria. Mechanistically, dimethyl fumarate (DMF)-a clinically available fumarate derivative-covalently modifies the phosphatase PPP1CB at cysteine 126, thereby blocking PPP1CB-mediated dephosphorylation of mitofusin 2 (MFN2), which in turn enhances mitophagy and ultimately preserves auditory function. These findings reveal that MSCs orchestrate mitochondrial replacement in damaged SGNs by delivering healthy mitochondria and facilitating the removal of impaired ones, underscoring the therapeutic potential of this strategy for treating SNHL related to mitochondrial dysfunction.