TY - JOUR
T1 - Pharmacological targeting of MCL-1 promotes mitophagy and improves disease pathologies in an Alzheimer’s disease mouse model
AU - Cen, Xufeng
AU - Chen, Yanying
AU - Xu, Xiaoyan
AU - Wu, Ronghai
AU - He, Fusheng
AU - Zhao, Qingwei
AU - Sun, Qiming
AU - Yi, Cong
AU - Wu, Jie
AU - Najafov, Ayaz
AU - Xia, Hongguang
N1 - Funding Information:
Financial support from the National Natural Science Foundation of China (No. 91854108, 81773182 and 31601121) and the National Key R&D Program of China (2017YFA0104200) is gratefully acknowledged. We thank professor Hui Yang from Institute of Neuroscience, Chinese Academy of Sciences for transgenic mt-Keima reporter mouse, professor Michael Lazarou from Monash University and professor Hanming Shen from National University of Singapore for HeLa WT and NDP52, p62, NBR1, and TAX1BP1 quadruple knockout cells. We thank the Imaging Center of Zhejiang University School of Medicine for assistance with confocal microscopy. We thank Chenyu Yang in the Center of Cryo-Electron Microscopy (CCEM), Zhejiang University for her technical assistance on TEM.
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12
Y1 - 2020/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85095874211&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85095874211&partnerID=8YFLogxK
U2 - 10.1038/s41467-020-19547-6
DO - 10.1038/s41467-020-19547-6
M3 - Article
C2 - 33184293
AN - SCOPUS:85095874211
SN - 2041-1723
VL - 11
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 5731
ER -