Zhang Jing, Wu Zuoxi, Long Zonghong, Feng Ceng, Bai Fuhai, Li Hong
Department of Anesthesiology, The Xinqiao Hospital, Army Medical University, Chongqing, China.
Department of Anesthesiology, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, China.
Mol Neurobiol. 2025 Jun 30. doi: 10.1007/s12035-025-05171-2.
Alzheimer's disease (AD) is a chronic neurodegenerative disorder and the most prevalent cause of dementia, yet it remains incurable. Ubiquinol-cytochrome c reductase core protein 1 (UQCRC1), a pivotal subunit of mitochondrial complex III, has been implicated in Alzheimer's disease pathogenesis, though its precise mechanistic contributions remain undefined. In this study, we systematically investigated the mechanistic involvement of UQCRC1 in AD pathogenesis. Our findings reveal significant downregulation of UQCRC1 expression in hippocampal tissues from both AD patients and APP/PS1 transgenic mice. Conditional UQCRC1 knockdown in AD model mice exacerbated cognitive deficits while transmission electron microscopy analysis demonstrated that UQCRC1 deficiency induces pathological lysosomal enlargement, lipofuscin accumulation, and increased neuronal apoptosis in hippocampal neurons. Mechanistic interrogation revealed that UQCRC1 depletion triggers lysosomal Ca⁺ overload-mediated proteolytic dysfunction coupled with activation of neuronal apoptotic pathways. Notably, adeno-associated virus-mediated UQCRC1 overexpression effectively reversed these pathological manifestations. Molecular dissection identified AMP-activated protein kinase (AMPK) signaling as the critical mechanistic mediator of this rescue effect, as pharmacological AMPK inhibition completely abrogated the therapeutic benefits. Together, our findings delineate a novel pathogenic axis linking mitochondrial complex III dysfunction to lysosomal degradation failure through UQCRC1-mediated AMPK regulation. These results position UQCRC1 not only as a promising biomarker for AD progression but also as a mechanistically validated therapeutic target, offering new insights into mitochondrial-lysosomal crosstalk in Alzheimer's disease pathology.
阿尔茨海默病（AD）是一种慢性神经退行性疾病，也是痴呆最常见的病因，但仍无法治愈。泛醇 - 细胞色素c还原酶核心蛋白1（UQCRC1）是线粒体复合物III的关键亚基，已被认为与阿尔茨海默病的发病机制有关，但其确切的机制作用仍不明确。在本研究中，我们系统地研究了UQCRC1在AD发病机制中的作用机制。我们的研究结果显示，AD患者和APP/PS1转基因小鼠海马组织中UQCRC1表达均显著下调。在AD模型小鼠中条件性敲低UQCRC1会加剧认知缺陷，而透射电子显微镜分析表明，UQCRC1缺乏会导致病理性溶酶体增大、脂褐素积累，并增加海马神经元的凋亡。机制研究表明，UQCRC1缺失会引发溶酶体Ca⁺过载介导的蛋白水解功能障碍，并激活神经元凋亡途径。值得注意的是，腺相关病毒介导的UQCRC1过表达有效逆转了这些病理表现。分子分析确定AMP激活的蛋白激酶（AMPK）信号是这种挽救作用的关键机制介质，因为药理学上抑制AMPK完全消除了治疗效果。总之，我们的研究结果描绘了一条新的致病轴，通过UQCRC1介导的AMPK调节将线粒体复合物III功能障碍与溶酶体降解失败联系起来。这些结果不仅将UQCRC1定位为AD进展的有希望的生物标志物，而且还将其定位为经过机制验证的治疗靶点，为阿尔茨海默病病理学中线粒体 - 溶酶体的相互作用提供了新的见解。
