title: Tau accumulation impairs mitophagy via increasing mitochondrial membrane potential and reducing mitochondrial Parkin.
abstract: 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.
authors.affiliation: 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.
authors.forename: Yu
authors.initials: Y
authors.lastname: Hu
authors.affiliation: 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.
authors.forename: Xia-Chun
authors.initials: XC
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Zhi-hao
authors.initials: ZH
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Yu
authors.initials: Y
authors.lastname: Luo
authors.affiliation: Department of Pharmacology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
authors.forename: Xiangnan
authors.initials: X
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Xiu-Ping
authors.initials: XP
authors.lastname: Liu
authors.affiliation: 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.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Feng
authors.affiliation: 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.
authors.forename: Qun
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Departments of Neurology and Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Yue
authors.affiliation: Department of Pharmacology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Keqiang
authors.initials: K
authors.lastname: Ye
authors.affiliation: 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.|Co-innovation Center of Neuroregeneration, Nantong University, Nantong, JS, China.
authors.forename: Jian-Zhi
authors.initials: JZ
authors.lastname: Wang
authors.affiliation: 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.|Co-innovation Center of Neuroregeneration, Nantong University, Nantong, JS, China.
authors.forename: Gong-Ping
authors.initials: GP
authors.lastname: Liu
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000378:metabolism*; D000818:Animals; D016022:Case-Control Studies; D057809:HEK293 Cells; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism / Q000502:physiology*; D063306:Mitophagy / Q000502:physiology; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D016875:tau Proteins / Q000378:metabolism*
chemical_list: C054369:MAPT protein, human; C558298:Mapt protein, mouse; D016875:tau Proteins; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein
keywords: Alzheimer’s disease; Gerotarget; PINK1; Parkin; mitophagy; tau