Human wild-type full-length tau accumulation disrupts mitochondrial dynamics and the functions via increasing mitofusins.

Xia-Chun Li,Keqiang Ye,Qiong Feng,Yao Zhang,Yu Luo,Qun Wang,Xiu-Ping Liu,Yu Hu,Zhi-Hao Wang,Gong-Ping Liu,Jian-Zhi Wang

doi:10.1038/srep24756

Abstract

Intracellular accumulation of tau protein is hallmark of sporadic Alzheimer’s disease (AD), however, the cellular mechanism whereby tau accumulation causes neurodegeneration is poorly understood. Here we report that overexpression of human wild-type full-length tau (termed htau) disrupted mitochondrial dynamics by enhancing fusion and induced their perinuclear accumulation in HEK293 cells and rat primary hippocampal neurons. The htau accumulation at later stage inhibited mitochondrial functions shown by the decreased ATP level, the ratio of ATP/ADP and complex I activity. Simultaneously, the cell viability was decreased with retraction of the cellular/neuronal processes. Further studies demonstrated that htau accumulation increased fusion proteins, including OPA1 and mitofusins (Mfn1, Mfn2) and reduced the ubiquitination of Mfn2. Downregulation of the mitofusins by shRNA to ~45% or ~52% of the control levels attenuated the htau-enhanced mitochondrial fusion and restored the functions, while downregulation of OPA1 to ~50% of the control level did not show rescue effects. Finally, abnormal mitochondrial accumulation and dysfunction were also observed in the brains of htau transgenic mice. Taken together, our data demonstrate that htau accumulation decreases cell viability and causes degeneration via enhancing mitofusin-associated mitochondrial fusion, which provides new insights into the molecular mechanisms underlying tauopathies.

Highlights

Of fusion proteins attenuates apoptosis[15]
We show that overexpression of htau protein disrupts mitochondrial dynamics and the functions with a correlated reduction of cell viability and neurodegeneration, the mechanisms involve an enhanced fusion by an increased mitofusin accumulation
We have previously reported that intracellular accumulation of tau affects cell viability[13]

Summary

Introduction

Of fusion proteins attenuates apoptosis[15] These observations suggest that intracellular accumulation of tau may cause neurodegeneration through disrupting mitochondrial functions, but the direct evidence for the role of wild-type full-length human tau in mitochondrial dynamic is still lacking. Mitochondria, as dynamic organelles, regulate cell viability and morphology of the synapses[16,17]. The mitochondrial dynamics determines mitochondrial morphology, size, distribution and functions[24] These observations suggest that intracellular accumulation of tau may antagonize acute apoptosis via modulating mitochondria fission/fusion and cause neurodegeneration through disrupting mitochondrial functions. We show that overexpression of htau protein disrupts mitochondrial dynamics and the functions with a correlated reduction of cell viability and neurodegeneration, the mechanisms involve an enhanced fusion by an increased mitofusin accumulation

Methods

Results

Conclusion