McGill Percy Kyle C, Liu Zunren, Qi Xin
Department of Physiology & Biophysics, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
Department of Physiology & Biophysics, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA; Center for Mitochondrial Research and Therapeutics, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
Neurotherapeutics. 2025 Apr;22(3):e00525. doi: 10.1016/j.neurot.2025.e00525. Epub 2025 Jan 17.
Alzheimer's disease (AD) is characterized by progressive neurodegeneration, marked by the accumulation of amyloid-β (Aβ) plaques and tau tangles. Emerging evidence suggests that mitochondrial dysfunction plays a pivotal role in AD pathogenesis, driven by impairments in mitochondrial quality control (MQC) mechanisms. MQC is crucial for maintaining mitochondrial integrity through processes such as proteostasis, mitochondrial dynamics, mitophagy, and precise communication with other subcellular organelles. In AD, disruptions in these processes lead to bioenergetic failure, gene dysregulation, the accumulation of damaged mitochondria, neuroinflammation, and lipid homeostasis impairment, further exacerbating neurodegeneration. This review elucidates the molecular pathways involved in MQC and their pathological relevance in AD, highlighting recent discoveries related to mitochondrial mechanisms underlying neurodegeneration. Furthermore, we explore potential therapeutic strategies targeting mitochondrial dysfunction, including gene therapy and pharmacological interventions, offering new avenues for slowing AD progression. The complex interplay between mitochondrial health and neurodegeneration underscores the need for innovative approaches to restore mitochondrial function and mitigate the onset and progression of AD.
阿尔茨海默病（AD）的特征是进行性神经退行性变，其标志是淀粉样β（Aβ）斑块和tau缠结的积累。新出现的证据表明，线粒体功能障碍在AD发病机制中起关键作用，这是由线粒体质量控制（MQC）机制受损驱动的。MQC对于通过蛋白质稳态、线粒体动力学、线粒体自噬以及与其他亚细胞器的精确通讯等过程维持线粒体完整性至关重要。在AD中，这些过程的破坏会导致生物能量衰竭、基因失调、受损线粒体的积累、神经炎症和脂质稳态受损，进一步加剧神经退行性变。本综述阐明了参与MQC的分子途径及其在AD中的病理相关性，强调了与神经退行性变潜在线粒体机制相关的最新发现。此外，我们探索了针对线粒体功能障碍的潜在治疗策略，包括基因治疗和药物干预，为减缓AD进展提供了新途径。线粒体健康与神经退行性变之间复杂的相互作用凸显了采用创新方法恢复线粒体功能并减轻AD发病和进展的必要性。
