Mitochondria sustain various essential functions at synaptic terminals. Synaptic mitochondria deficits have been implicated in early Alzheimer disease (AD) pathophysiology. Mitophagy, a selective autophagy for removal of damaged mitochondria, plays a key role in mitochondrial quality control in neurons. However, fundamental questions remain unanswered as to whether mitophagy regulates synaptic mitochondrial integrity and whether AD-associated early deficits in synaptic mitochondria are attributed to mitophagy failure. We have recently revealed that the integrity of synaptic mitochondria is maintained by a coordination of RHEB-mediated mitophagy with dynein- and SNAPIN-driven retrograde transport. We demonstrate that increased mitophagy initiation, coupled with defective retrograde transport, triggers mitophagy stress at AD synapses. Excitingly, SNAPIN-enhanced retrograde transport reduces synaptic mitophagy stress and ameliorates mitochondrial deficits, thereby counteracting synaptic damage in AD mouse brains. Therefore, our study provides new mechanistic insights into how mitophagy facilitates synaptic mitochondrial maintenance and how mitophagy failure exacerbates AD-linked mitochondrial defects and synaptic degeneration.

Abbreviation: AD: Alzheimer disease; Aβ: amyloid-β; APP: amyloid beta precursor protein; CCCP: carbonyl cyanide m-chlorophenylhydrazone; LE: late endosome; Δψ_m, mitochondrial membrane potential; RHEB: Ras homolog enriched in brain; RNAi: RNA interference; shRNA: small hairpin RNA; Tg: transgenic

线粒体在突触末梢维持各种基本功能。突触线粒体缺陷与早期阿尔茨海默病 (AD) 的病理生理学有关。Mitophagy 是一种用于去除受损线粒体的选择性自噬，在神经元线粒体质量控制中起着关键作用。然而，关于线粒体自噬是否调节突触线粒体完整性以及突触线粒体中 AD 相关的早期缺陷是否归因于线粒体自噬失败，这些基本问题仍未得到解答。我们最近发现，突触线粒体的完整性是通过 RHEB 介导的线粒体自噬与动力蛋白和 SNAPIN 驱动的逆行运输的协调来维持的。我们证明增加的线粒体自噬启动，加上有缺陷的逆行运输，会触发 AD 突触的线粒体自噬压力。令人兴奋的是，SNAPIN 增强的逆行运输减少突触线粒体自噬应激并改善线粒体缺陷，从而抵消 AD 小鼠大脑中的突触损伤。因此，我们的研究为线粒体自噬如何促进突触线粒体维持以及线粒体自噬失败如何加剧 AD 相关的线粒体缺陷和突触退化提供了新的机制见解。

缩写：AD：阿尔茨海默病；Aβ：淀粉样蛋白-β；APP：淀粉样β前体蛋白；CCCP：羰基氰化物米-chlorophenylhydrazone; LE：晚期内体；Δψ _m，线粒体膜电位；RHEB：大脑中富含的Ras同源物；RNAi：RNA干扰；shRNA：小发夹RNA；Tg：转基因