Synaptic mitochondria are particularly vulnerable to physiological insults, and defects in synaptic mitochondria are linked to early pathophysiology of Alzheimer's disease (AD). Mitophagy, a cargo‐specific autophagy for elimination of dysfunctional mitochondria, constitutes a key quality control mechanism. However, how mitophagy ensures synaptic mitochondrial integrity remains largely unknown. Here, we reveal Rheb and Snapin as key players regulating mitochondrial homeostasis at synapses. Rheb initiates mitophagy to target damaged mitochondria for autophagy, whereas dynein–Snapin‐mediated retrograde transport promotes clearance of mitophagosomes from synaptic terminals. We demonstrate that synaptic accumulation of mitophagosomes is a feature in AD‐related mutant hAPP mouse brains, which is attributed to increased mitophagy initiation coupled with impaired removal of mitophagosomes from AD synapses due to defective retrograde transport. Furthermore, while deficiency in dynein–Snapin‐mediated retrograde transport recapitulates synaptic mitophagy stress and induces synaptic degeneration, elevated Snapin expression attenuates mitochondrial defects and ameliorates synapse loss in AD mouse brains. Taken together, our study provides new insights into mitophagy regulation of synaptic mitochondrial integrity, establishing a foundation for mitigating AD‐associated mitochondria deficits and synaptic damage through mitophagy enhancement.

中文翻译：

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线粒体自噬调节突触中线粒体的完整性，对突触维持至关重要。

突触线粒体特别容易受到生理损伤，突触线粒体的缺陷与阿尔茨海默病 (AD) 的早期病理生理学有关。Mitophagy 是一种用于消除功能失调的线粒体的货物特异性自噬，是一种关键的质量控制机制。然而，线粒体自噬如何确保突触线粒体完整性在很大程度上仍然未知。在这里，我们揭示了 Rheb 和 Snapin 作为调节突触线粒体稳态的关键参与者。Rheb 启动线粒体自噬以靶向受损线粒体进行自噬，而动力蛋白-Snapin 介导的逆行运输促进线粒体自突触末梢的清除。我们证明了线粒体吞噬体的突触积累是 AD 相关突变 hAPP 小鼠大脑中的一个特征，这归因于线粒体自噬起始增加以及由于逆行运输缺陷导致的线粒体自噬体从 AD 突触中的去除受损。此外，虽然动力蛋白-Snapin 介导的逆行运输不足会重现突触线粒体自噬应激并诱导突触变性，但 Snapin 表达升高会减轻 AD 小鼠大脑中的线粒体缺陷并改善突触丢失。总之，我们的研究为突触线粒体完整性的线粒体自噬调节提供了新的见解，为通过线粒体自噬增强减轻 AD 相关的线粒体缺陷和突触损伤奠定了基础。虽然动力蛋白-Snapin 介导的逆行运输缺陷会重现突触线粒体自噬应激并诱导突触变性，但 Snapin 表达升高会减弱 AD 小鼠大脑中的线粒体缺陷并改善突触损失。总之，我们的研究为突触线粒体完整性的线粒体自噬调节提供了新的见解，为通过线粒体自噬增强减轻 AD 相关的线粒体缺陷和突触损伤奠定了基础。虽然动力蛋白-Snapin 介导的逆行运输缺陷会重现突触线粒体自噬应激并诱导突触变性，但 Snapin 表达升高会减弱 AD 小鼠大脑中的线粒体缺陷并改善突触损失。总之，我们的研究为突触线粒体完整性的线粒体自噬调节提供了新的见解，为通过线粒体自噬增强减轻 AD 相关的线粒体缺陷和突触损伤奠定了基础。