Watanabe Seiji, Yamanaka Koji
Department of Neuroscience and Pathobiology, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Aichi, Japan.
Department of Neuroscience and Pathobiology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
Bioessays. 2025 May 4:e70016. doi: 10.1002/bies.70016.
Recent evidence indicates that the mitochondria-endoplasmic reticulum (ER) contact site is a novel microdomain essential for cellular homeostasis. Various proteins are accumulated at the mitochondria-associated membrane (MAM), an ER subcomponent closely associated with the mitochondria, contributing to Ca transfer to the mitochondria, lipid synthesis, mitochondrial fission/fusion, and autophagy. These functions are disrupted in the diseases, particularly in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and Alzheimer's disease. In this review, we summarize the disruption of protein homeostasis in various neurodegenerative diseases, present recent works on the mechanisms of MAM aberration, including ours mainly focused on ALS, and then discuss challenges and prospects for future MAM-targeted therapies in neurodegenerative diseases.
最近的证据表明，线粒体-内质网（ER）接触位点是细胞内稳态所必需的新型微区。多种蛋白质聚集在线粒体相关膜（MAM）上，MAM是与线粒体紧密相关的内质网亚成分，有助于钙向线粒体的转运、脂质合成、线粒体裂变/融合及自噬。这些功能在疾病中会受到破坏，尤其是在诸如肌萎缩侧索硬化症（ALS）和阿尔茨海默病等神经退行性疾病中。在本综述中，我们总结了各种神经退行性疾病中蛋白质稳态的破坏情况，介绍了包括我们主要聚焦于ALS的关于MAM异常机制的近期研究工作，然后讨论了神经退行性疾病中未来以MAM为靶点的治疗面临的挑战和前景。
