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Author Notes:

Correspondence to: Jian-Zhi Wang, email: wangjz@mails.tjmu.edu.cn; Gong-Ping Liu,Email: liugp111@mail.hust.edu.cn

J.Z.W., and G.P.L. designed research; Y.H., X.C.L.,Z.H.W., Y.L., X.P.L., Q.F., X.Z. and Q.W. performed experiments; X.C.L., Y.H., Z.C., Z.Y., K.Y., G.P.L., and J.Z.W. analyzed data. J.Z.W., G.P.L., and K.Y., wrote the paper.

All authors disclose: (a) no actual or potential conflicts of interest including any financial, personal or other relationships with other people or organizations within three years of beginning the work submitted that could inappropriately influence (bias) their work.

(b) When applicable, provide statements verifying that appropriate approval and procedures were used concerning animals.


Research Funding:

This work was supported in parts by National Natural Science Foundation of China (81171195, 91132305, 81271402, 81261120570 and 81528007).


  • Science & Technology
  • Life Sciences & Biomedicine
  • Oncology
  • Cell Biology
  • tau
  • mitophagy
  • PINK1
  • Parkin
  • Alzheimer's disease
  • Gerotarget
  • A-BETA

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

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Journal Title:



Volume 7, Number 14


, Pages 17356-17368

Type of Work:

Article | Final Publisher PDF


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 PTENinduced 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.

Copyright information:

© 2016 Hu et al.

This is an Open Access work distributed under the terms of the Creative Commons Attribution 3.0 Unported License (http://creativecommons.org/licenses/by/3.0/).

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