Research Papers: Gerotarget (Focus on Aging):

Tau accumulation impairs mitophagy via increasing mitochondrial membrane potential and reducing mitochondrial Parkin

Yu Hu, Xia-Chun Li, Zhi-hao Wang, Yu Luo, Xiangnan Zhang, Xiu-Ping Liu, Qiong Feng, Qun Wang, Zhenyu Yue, Zhong Chen, Keqiang Ye, Jian-Zhi Wang and Gong-Ping Liu _

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Oncotarget. 2016; 7:17356-17368. https://doi.org/10.18632/oncotarget.7861

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Yu Hu1,*, Xia-Chun Li1,*, Zhi-hao Wang1, Yu Luo1, Xiangnan Zhang2, Xiu-Ping Liu1, Qiong Feng1, Qun Wang1, Zhenyu Yue3, Zhong Chen2, Keqiang Ye4, Jian-Zhi Wang1,5 and Gong-Ping Liu1,5

1 Department of Pathophysiology, School of Basic Medicine and The Collaborative Innovation Center for Brain Science, Key Laboratory of Ministry of Education of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

2 Department of Pharmacology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China

3 Departments of Neurology and Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

4 Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA

5 Co-innovation Center of Neuroregeneration, Nantong University, Nantong, JS, China

These authors have contributed equally to this work

Correspondence to:

Jian-Zhi Wang, email:

Gong-Ping Liu, email:

Keywords: tau, mitophagy, PINK1, Parkin, Alzheimer’s disease, Gerotarget

Received: November 15, 2015 Accepted: February 25, 2016 Published: March 02, 2016


Intracellular accumulation of wild type tau is a hallmark of sporadic Alzheimer’s disease (AD). However, the molecular mechanisms underlying tau toxicity is not fully understood. Here, we detected mitophagy deficits evidenced by the increased levels of mitophagy markers, including COX IV, TOMM20, and the ratio of mtDNA to genomic DNA indexed as mt-Atp6/Rpl13, in the AD brains and in the human wild type full-length tau (htau) transgenic mice. More interestingly, the mitophagy deficit was only shown in the AD patients who had an increased total tau level. Further studies demonstrated that overexpression of htau induced mitophagy deficits in HEK293 cells, the primary hippocampal neurons and in the brains of C57 mice. Upon overexpression of htau, the mitochondrial membrane potential was increased and the levels of PTEN-induced kinase 1 (PINK1) and Parkin decreased in the mitochondrial fraction, while upregulation of Parkin attenuated the htau-induced mitophagy deficits. Finally, we detected a dose-dependent allocation of tau proteins into the mitochondrial outer membrane fraction along with its cytoplasmic accumulation. These data suggest that intracellular accumulation of htau induces mitophagy deficits by direct inserting into the mitochondrial membrane and thus increasing the membrane potential, which impairs the mitochondrial residence of PINK1/Parkin. Our findings reveal a novel mechanism underlying the htau-induced neuronal toxicities in AD and other tauopathies.

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