PINK1相关线粒体自噬通过调控ACSL4的亚细胞分布保护免受顺铂诱导的耳毒性

文献信息

中文摘要

背景： 顺铂诱导的耳毒性是一个重要的临床问题，与铁死亡和线粒体自噬功能障碍有关。本研究使用体外培养的原代大鼠耳蜗边缘细胞和体内顺铂诱导耳毒性的C57BL/6J小鼠模型，探讨线粒体自噬如何调控顺铂诱导听力损失中的铁死亡。方法：未标注。结果：顺铂抑制PTEN诱导的推定激酶1（PINK1）通路，损害线粒体自噬，并引发以铁过载、脂质过氧化、酰基辅酶A合成酶长链家族成员4（ACSL4）增加和谷胱甘肽过氧化物酶4减少为特征的铁死亡。药理学激活线粒体自噬或PINK1过表达在体外减轻铁死亡，而去铁胺治疗在体内减少顺铂诱导的听力损失和血-迷路屏障损伤。机制上，线粒体自噬的恢复与ACSL4线粒体靶向增加和胞质积累减少相关，可能通过线粒体自噬清除实现，从而抑制铁死亡。结论：这些发现支持一个模型，即PINK1相关线粒体自噬受损导致胞质ACSL4积累和铁死亡损伤。调节线粒体自噬和ACSL4亚细胞分布可能是减轻顺铂诱导耳毒性的潜在策略。

英文摘要

Cisplatin-induced ototoxicity is a significant clinical issue linked to ferroptosis and mitophagy dysfunction. This study investigated how mitophagy regulates ferroptosis in cisplatin-induced hearing loss using cultured primary rat cochlear marginal cells in vitro and a C57BL/6J mouse model of cisplatin-induced ototoxicity in vivo. Cisplatin suppressed the PTEN-induced putative kinase 1 (PINK1) pathway, impaired mitophagy, and triggered ferroptosis characterized by iron overload, lipid peroxidation, increased acyl-CoA synthetase long-chain family member 4 (ACSL4), and decreased glutathione peroxidase 4. Pharmacological activation of mitophagy or PINK1 overexpression alleviated ferroptosis in vitro, while deferoxamine treatment reduced cisplatin-induced hearing loss and blood-labyrinth barrier damage in vivo. Mechanistically, restoration of mitophagy was associated with increased mitochondrial targeting and reduced cytosolic accumulation of ACSL4, potentially through mitophagic clearance, thereby suppressing ferroptosis. These findings support a model in which impaired PINK1-associated mitophagy contributes to cytosolic ACSL4 accumulation and ferroptotic injury. Modulating mitophagy and ACSL4 subcellular distribution may represent a potential strategy for mitigating cisplatin-induced ototoxicity.