粒体自噬
自噬
体内
细胞凋亡
激活剂(遗传学)
线粒体
药品
细胞生物学
药物发现
疾病
生物
药理学
医学
癌症研究
受体
神经科学
生物信息学
内科学
生物化学
遗传学
作者
Xufeng Cen,Yanying Chen,Xiaoyan Xu,Ronghai Wu,Fusheng He,Qiu Zhao,Qiming Sun,Cong Yi,Jie Wu,Ayaz Najafov,Hongguang Xia
标识
DOI:10.1038/s41467-020-19547-6
摘要
Abstract There is increasing evidence that inducing neuronal mitophagy can be used as a therapeutic intervention for Alzheimer’s disease. Here, we screen a library of 2024 FDA-approved drugs or drug candidates, revealing UMI-77 as an unexpected mitophagy activator. UMI-77 is an established BH3-mimetic for MCL-1 and was developed to induce apoptosis in cancer cells. We found that at sub-lethal doses, UMI-77 potently induces mitophagy, independent of apoptosis. Our mechanistic studies discovered that MCL-1 is a mitophagy receptor and directly binds to LC3A. Finally, we found that UMI-77 can induce mitophagy in vivo and that it effectively reverses molecular and behavioral phenotypes in the APP/PS1 mouse model of Alzheimer’s disease. Our findings shed light on the mechanisms of mitophagy, reveal that MCL-1 is a mitophagy receptor that can be targeted to induce mitophagy, and identify MCL-1 as a drug target for therapeutic intervention in Alzheimer’s disease.
科研通智能强力驱动
Strongly Powered by AbleSci AI