Dysregulation of autophagosome–mitochondria contacts contributes to autophagy dysfunction and neurodegeneration in tauopathy
Abstract
Mitochondria (Mito) engage in extensive communication with other organelles through membrane contacts. Perturbed mitochondria–organelle interactions are indicated in a variety of neurodegenerative diseases, but the underlying mechanisms remain poorly understood. Here, we report a class of mitochondria–organelle communication: autophagosome/autophagic vacuole (AV)–Mito contact, which exhibits hypertethering in tauopathy neurons, consequently hampering AV retrograde transport. Such defects are attributed to accelerated turnover of the contact release factor TBC1D15, triggered by mitochondrial bioenergetic deficit-induced hyperactivity of the adenosine monophosphate-activated protein kinase (AMPK). Increasing TBC1D15 levels or repressing AMPK activity normalizes AV-Mito contact release and restores retrograde transport of AVs, thereby increasing autophagic cargo clearance and reducing tau burden in tauopathy axons. Furthermore, overexpression of TBC1D15 enhances autophagic clearance and attenuates tau pathology, alleviating neurodegeneration and cognitive dysfunction in tauopathy mice. Taken together, our study provides mechanistic insights into AV-Mito contact dysregulation in tauopathy-related autophagy failure, laying the groundwork for the development of potential therapeutics to combat tauopathy diseases.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (14)
Nuo Jia
Division of Life Sciences, Department of Cell Biology and Neuroscience, School of Arts and Sciences, Rutgers, The State University of New Jersey
Hongyuan Guan
Division of Life Sciences, Department of Cell Biology and Neuroscience, School of Arts and Sciences, Rutgers, The State University of New Jersey
Yantao Zuo
Division of Life Sciences, Department of Cell Biology and Neuroscience, School of Arts and Sciences, Rutgers, The State University of New Jersey
Yu Young Jeong
Division of Life Sciences, Department of Cell Biology and Neuroscience, School of Arts and Sciences, Rutgers, The State University of New Jersey
Niharika Amireddy
Division of Life Sciences, Department of Cell Biology and Neuroscience, School of Arts and Sciences, Rutgers, The State University of New Jersey
Gavesh Rajapaksha
Division of Life Sciences, Department of Cell Biology and Neuroscience, School of Arts and Sciences, Rutgers, The State University of New Jersey
Cuauhtemoc Ulises Gonzalez
Division of Life Sciences, Department of Cell Biology and Neuroscience, School of Arts and Sciences, Rutgers, The State University of New Jersey
Nora Jaber
Division of Life Sciences, Department of Cell Biology and Neuroscience, School of Arts and Sciences, Rutgers, The State University of New Jersey
Yun-Kyung Lee
Division of Life Sciences, Department of Cell Biology and Neuroscience, School of Arts and Sciences, Rutgers, The State University of New Jersey
Marialaina Nissenbaum
Department of Psychology, School of Arts and Sciences, Rutgers, The State University of New Jersey
David J. Margolis
Division of Life Sciences, Department of Cell Biology and Neuroscience, School of Arts and Sciences, Rutgers, The State University of New Jersey
Wei Dai
Université Paris Cité, Institut de Physique du Globe de Paris, CNRS
Alexander W. Kusnecov
Department of Psychology, School of Arts and Sciences, Rutgers, The State University of New Jersey
Qian Cai
State Key Laboratory of Functional Crystals and Devices, Fujian Institute of Research on the Structure of Matter