Center for Healthy Aging, Department of Cellular and Molecular Medicine, University of Copenhagen, DK-2200, Copenhagen, Denmark.
Department of Health Sciences, University Magna Græcia of Catanzaro, 88100, Catanzaro, Italy.
Free Radic Biol Med. 2024 Sep;222:569-578. doi: 10.1016/j.freeradbiomed.2024.07.013. Epub 2024 Jul 14.
Mitophagy is a mechanism that maintains mitochondrial integrity and homeostasis and is thought to promote longevity and reduce the risk of age-related neurodegenerative diseases, including Alzheimer's disease (AD). Here, we investigate the abundance of mitochondrial reactive oxygen species (ROS), mitochondrial function, and mitophagy in primary fibroblasts from patients with sporadic AD (sAD) and normal healthy controls. The results show increased levels of mitochondrial ROS, changes in mitochondrial morphology, altered bioenergetic properties, and defects in autophagy, mitophagy, and lysosome-mediated degradation pathways in sAD fibroblasts relative to control fibroblasts. Interestingly, lysosome abundance and the staining of lysosomal markers remained high, while the capacity of lysosome-dependent degradation was lower in sAD fibroblasts than in controls fibroblasts. Nicotinamide riboside supplementation decreased mitochondrial ROS, while capacity for lysosomal degradation remained unchanged in sAD fibroblasts relative to healthy control fibroblasts. These findings provide insight into molecular mechanisms involving the dysregulation of lysosome and autophagy/mitophagy pathways that may contribute significantly to clinical signs and pathological features of sAD.
自噬是一种维持线粒体完整性和动态平衡的机制，被认为可以促进长寿和降低与年龄相关的神经退行性疾病（包括阿尔茨海默病）的风险。在这里，我们研究了散发性阿尔茨海默病（sAD）患者和正常健康对照者的原代成纤维细胞中线粒体活性氧（ROS）、线粒体功能和自噬的丰度。结果表明，与对照成纤维细胞相比，sAD 成纤维细胞中线粒体 ROS 水平升高，线粒体形态发生变化，生物能量特性改变，自噬、自噬和溶酶体介导的降解途径缺陷。有趣的是，sAD 成纤维细胞中的溶酶体丰度和溶酶体标志物染色仍然很高，而溶酶体依赖性降解的能力低于对照成纤维细胞。烟酰胺核苷补充剂降低了线粒体 ROS，而 sAD 成纤维细胞相对于健康对照成纤维细胞的溶酶体降解能力保持不变。这些发现为涉及溶酶体和自噬/自噬途径失调的分子机制提供了深入了解，这些机制可能对 sAD 的临床症状和病理特征有重要贡献。
