Tau protein as a regulator of mitochondrial function and dynamics
Abstract
Mitochondrial damage is a shared hallmark of brain aging and neurodegeneration. While pathological Tau mutations disrupt mitochondrial dynamics and function, the physiological role of wild-type (WT) Tau in the maintenance of mitochondrial homeostasis remains poorly understood. Here, using Caenorhabditis elegans and mice lacking PTL-1, the nematode Tau-like homolog, and Tau respectively, we demonstrate that Tau deficiency promotes a shift toward a pro-fusion mitochondrial state associated with enhanced mitochondrial function and stress resistance. In both models, loss of Tau leads to increased mitochondrial activity and altered redox homeostasis, while it enhances resistance to heat and mitochondrial stress in C. elegans . Strikingly, loss of FZO-1, the mitofusin homolog, abolishes the beneficial phenotypes, whereas its overexpression phenocopies key aspects of Tau/PTL-1 deficiency. Together, our findings uncover a conserved role for WT Tau in restraining mitochondrial fusion and functional adaptation, highlighting its contribution to mitochondrial homeostasis and cellular stress responses.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (19)
Eleni Tsakiri
Department of Physiology, Medical School, National and Kapodistrian University of Athens
Carlos Campos-Marques
Life and Health Sciences Research Institute (ICVS), University of Minho
Christina Ploumi
Department of Physiology, Medical School, National and Kapodistrian University of Athens
Kalliopi Skourti
Laboratory of Brain exosomes and Pathology - ExoBrain, Institute of Biosciences and Applications, National Centre for Scientific Research Demokritos
Antonis Roussos
Department of Physiology, Medical School, National and Kapodistrian University of Athens
Eirini Mytilinaiou
Department of Physiology, Medical School, National and Kapodistrian University of Athens
Anastasia Vamvaka Iakovou
Laboratory of Brain exosomes and Pathology - ExoBrain, Institute of Biosciences and Applications, National Centre for Scientific Research Demokritos
Ildete Luísa Ferreira
Center for Neuroscience and Cell Biology, University of Coimbra
Chrysoula Dioli
Life and Health Sciences Research Institute (ICVS), University of Minho
Despoina D. Gianniou
Department of Biology, National and Kapodistrian University of Athens
Martina Samiotaki
Institute for Bioinnovation, Biomedical Sciences Research Center “Alexander Fleming”
Jonas Campos
Life and Health Sciences Research Institute (ICVS), University of Minho
Clarissa Waites
Department of Pathology and Cell Biology, Taub Institute for Research on Alzheimer’s Disease and Aging Brain, Columbia University Irving Medical Center
Nuno Sousa
Centro Universitário de Jaguariúna
Ioannis P. Trougakos
Department of Biology, National and Kapodistrian University of Athens
Joana M. Silva
Life and Health Sciences Research Institute (ICVS), University of Minho
A. Cristina Rego
Center for Neuroscience and Cell Biology, University of Coimbra
Ioannis Sotiropoulos
Life and Health Sciences Research Institute (ICVS), University of Minho
Konstantinos Palikaras
Department of Physiology, Medical School, National and Kapodistrian University of Athens