Takeda Keisuke, Uda Aoi, Mitsubori Mikihiro, Nagashima Shun, Iwasaki Hiroko, Ito Naoki, Shiiba Isshin, Ishido Satoshi, Matsuoka Masaaki, Inatome Ryoko, Yanagi Shigeru
Laboratory of Molecular Biochemistry, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan.
Department of Biology, University of Padova, Padova, Italy.
Commun Biol. 2021 Feb 12;4(1):192. doi: 10.1038/s42003-021-01720-2.
Mitochondrial pathophysiology is implicated in the development of Alzheimer's disease (AD). An integrative database of gene dysregulation suggests that the mitochondrial ubiquitin ligase MITOL/MARCH5, a fine-tuner of mitochondrial dynamics and functions, is downregulated in patients with AD. Here, we report that the perturbation of mitochondrial dynamics by MITOL deletion triggers mitochondrial impairments and exacerbates cognitive decline in a mouse model with AD-related Aβ pathology. Notably, MITOL deletion in the brain enhanced the seeding effect of Aβ fibrils, but not the spontaneous formation of Aβ fibrils and plaques, leading to excessive secondary generation of toxic and dispersible Aβ oligomers. Consistent with this, MITOL-deficient mice with Aβ etiology exhibited worsening cognitive decline depending on Aβ oligomers rather than Aβ plaques themselves. Our findings suggest that alteration in mitochondrial morphology might be a key factor in AD due to directing the production of Aβ form, oligomers or plaques, responsible for disease development.
线粒体病理生理学与阿尔茨海默病（AD）的发生发展有关。一个基因失调综合数据库表明，线粒体泛素连接酶MITOL/MARCH5作为线粒体动力学和功能的微调器，在AD患者中表达下调。在此，我们报告，在具有AD相关Aβ病理的小鼠模型中，MITOL缺失引起的线粒体动力学扰动会引发线粒体损伤并加剧认知衰退。值得注意的是，大脑中MITOL缺失增强了Aβ纤维的播种效应，但不影响Aβ纤维和斑块的自发形成，导致有毒且可分散的Aβ寡聚体过度二次生成。与此一致的是，具有Aβ病因的MITOL缺陷小鼠表现出认知衰退恶化，这取决于Aβ寡聚体而非Aβ斑块本身。我们的研究结果表明，线粒体形态改变可能是AD的一个关键因素，因为它指导了Aβ形式、寡聚体或斑块的产生，而这些与疾病发展有关。
