Nakamura Yoki, Nakano Manaya, Hisaoka-Nakashima Kazue, Morioka Norimitsu
Department of Pharmacology, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan.
J Clin Biochem Nutr. 2025 May;76(3):239-244. doi: 10.3164/jcbn.24-202. Epub 2025 Mar 11.
Microglia, the primary immune cells of the central nervous system, play a pivotal role in maintaining brain homeostasis. Recent studies have highlighted the involvement of microglial dysfunction in the pathogenesis of various age-related neurodegenerative diseases, such as Alzheimer's disease. Moreover, the metabolic state of microglia has emerged as a key factor in these diseases. Interestingly, aging and neurodegenerative diseases are associated with impaired mitochondrial function and a metabolic shift from oxidative phosphorylation to glycolysis in microglia. This metabolic shift may contribute to sustained microglial activation and neuroinflammation. Furthermore, the leakage of mitochondrial DNA into the cytoplasm, because of mitochondrial dysfunction, has been implicated in triggering inflammatory responses and disrupting brain function. This review summarizes recent advances in understanding the role of microglial metabolic shifts, particularly glycolysis, and mitochondrial dysfunction. It also explores the potential of targeting microglial metabolism, for instance by modulating mitophagy or intervening in specific metabolic pathways, as a novel therapeutic approach for changes in brain function and neurodegenerative diseases associated with aging.
小胶质细胞是中枢神经系统的主要免疫细胞，在维持大脑内环境稳定中起关键作用。最近的研究强调了小胶质细胞功能障碍在各种与年龄相关的神经退行性疾病（如阿尔茨海默病）发病机制中的作用。此外，小胶质细胞的代谢状态已成为这些疾病的关键因素。有趣的是，衰老和神经退行性疾病与小胶质细胞线粒体功能受损以及代谢从氧化磷酸化向糖酵解转变有关。这种代谢转变可能导致小胶质细胞持续激活和神经炎症。此外，由于线粒体功能障碍，线粒体DNA泄漏到细胞质中，与引发炎症反应和破坏脑功能有关。本综述总结了在理解小胶质细胞代谢转变（特别是糖酵解）和线粒体功能障碍作用方面的最新进展。它还探讨了靶向小胶质细胞代谢的潜力，例如通过调节线粒体自噬或干预特定代谢途径，作为一种针对与衰老相关的脑功能变化和神经退行性疾病的新型治疗方法。
