Human wild-type full-length tau accumulation disrupts mitochondrial dynamics and the functions via increasing mitofusins.
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.
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 430030, China.|Department of Physiology and Pathophysiology, Medical School, China Three Gorges University, Yichang 443002, China.
Xia-Chun
XC
Li
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 430030, China.
Yu
Y
Hu
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 430030, China.
Zhi-hao
ZH
Wang
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 430030, China.|Institute of Pathophysiology, School of Basic Medical Sciences, Lanzhou University, Lanzhou 730000, China.
Yu
Y
Luo
Endocrine Department, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Yao
Y
Zhang
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 430030, China.
Xiu-Ping
XP
Liu
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 430030, China.
Qiong
Q
Feng
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 430030, China.
Qun
Q
Wang
Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA30322, USA.
Keqiang
K
Ye
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 430030, China.|Co-innovation Center of Neuroregeneration, Nantong University, Nantong 226001, China.
Gong-Ping
GP
Liu
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 430030, China.|Co-innovation Center of Neuroregeneration, Nantong University, Nantong 226001, China.
Jian-Zhi
JZ
Wang
D002470:Cell Survival / Q000235:genetics; D020558:GTP Phosphohydrolases / Q000378:metabolism; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D008928:Mitochondria / Q000235:genetics* / Q000378:metabolism*; D063154:Mitochondrial Dynamics / Q000235:genetics*; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D054875:Ubiquitination; D016875:tau Proteins / Q000235:genetics* / Q000378:metabolism*
D033681:Mitochondrial Membrane Transport Proteins; D024101:Mitochondrial Proteins; D016875:tau Proteins; D020558:GTP Phosphohydrolases; C470018:MFN2 protein, human