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

• Authors: Xia-Chun Li, Huazhong University of Science and Technology; Yu Hu, Huazhong University of Science and Technology; Zhi-hao Wang, Huazhong University of Science and Technology; Yu Luo, Huazhong University of Science and Technology; Yao Zhang, Huazhong University of Science and Technology; Xiu-Ping Liu, Huazhong University of Science and Technology; Qiong Feng, Huazhong University of Science and Technology; Qun Wang, Huazhong University of Science and Technology; Keqiang Ye, Emory University; Gong-Ping Liu, Huazhong University of Science and Technology; Jian-Zhi Wang, Huazhong University of Science and Technology
• Journal Title: Scientific Reports
• Volume: Volume 6
• Publisher: Nature Publishing Group | 2016-04-21, Pages 24756-24756
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1038/srep24756
• Subjects: Health Sciences, Pathology; Biology, Physiology

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.