TY - JOUR
T1 - BRCA1 Deficiency Impairs Mitophagy and Promotes Inflammasome Activation and Mammary Tumor Metastasis
AU - Chen, Qiang
AU - Lei, Josh Haipeng
AU - Bao, Jiaolin
AU - Wang, Haitao
AU - Hao, Wenhui
AU - Li, Licen
AU - Peng, Cheng
AU - Masuda, Takaaki
AU - Miao, Kai
AU - Xu, Jun
AU - Xu, Xiaoling
AU - Deng, Chu Xia
N1 - Funding Information:
The authors thank the members of the Deng laboratory for critical discussions. This work was supported by National Natural Science Foundation of China (81672603 and 81401978) granted to Q.C. and by the Chair Professor Grant (CPG 2017‐00016‐FHS) and Startup Research Grant (SRG 2017‐00045‐FHS) granted to C.‐X.D. by University of Macau, Macau SAR, China as well as by Macao Science and Technology Development Fund grant (065/2015/A2, 094/2015/A3, and 0011/2019/AKP) granted to C.‐X.D.
Publisher Copyright:
© 2020 The Authors. Published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
PY - 2020/3/1
Y1 - 2020/3/1
N2 - The breast cancer susceptibility gene 1 (BRCA1) is a major tumor suppressor gene and is most frequently mutated in hereditary breast cancer. BRCA1 plays a critical role in many biological processes, especially maintaining genomic stability in the nucleus, yet its role in the cytoplasm remains elusive. Here, it is revealed that BRCA1 maintains a healthy mitochondrial network through regulating mitochondrial dynamics, including fission and fusion. BRCA1 deficiency causes dysfunctional mitochondrial dynamics through increased expression of mitofusin1/2. With mitochondrial stress, BRCA1 is recruited to the mitochondrial outer membrane, where it plays an essential role in maintaining a healthy mitochondrial network. Consequently, BRCA1 deficiency impairs stress-induced mitophagy through blocking ataxia-telangiectasia mutated (ATM)-AMP-activated protein kinase (AMPK)-Dynamin-related protein 1 (DRP1)-mediated mitochondrial fission and triggers NLRP3 inflammasome activation, which creates a tumor-associated microenvironment, thereby facilitating tumor proliferation and metastasis. It is further shown that inflammasome inhibition can prevent tumor recurrence and metastasis. This study uncovers an important role of BRCA1 in regulating mitophagy and suggests a therapeutic approach for fighting this deadly disease.
AB - The breast cancer susceptibility gene 1 (BRCA1) is a major tumor suppressor gene and is most frequently mutated in hereditary breast cancer. BRCA1 plays a critical role in many biological processes, especially maintaining genomic stability in the nucleus, yet its role in the cytoplasm remains elusive. Here, it is revealed that BRCA1 maintains a healthy mitochondrial network through regulating mitochondrial dynamics, including fission and fusion. BRCA1 deficiency causes dysfunctional mitochondrial dynamics through increased expression of mitofusin1/2. With mitochondrial stress, BRCA1 is recruited to the mitochondrial outer membrane, where it plays an essential role in maintaining a healthy mitochondrial network. Consequently, BRCA1 deficiency impairs stress-induced mitophagy through blocking ataxia-telangiectasia mutated (ATM)-AMP-activated protein kinase (AMPK)-Dynamin-related protein 1 (DRP1)-mediated mitochondrial fission and triggers NLRP3 inflammasome activation, which creates a tumor-associated microenvironment, thereby facilitating tumor proliferation and metastasis. It is further shown that inflammasome inhibition can prevent tumor recurrence and metastasis. This study uncovers an important role of BRCA1 in regulating mitophagy and suggests a therapeutic approach for fighting this deadly disease.
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U2 - 10.1002/advs.201903616
DO - 10.1002/advs.201903616
M3 - Article
AN - SCOPUS:85079461150
SN - 2198-3844
VL - 7
JO - Advanced Science
JF - Advanced Science
IS - 6
M1 - 1903616
ER -
