Year: 2026
Type: article
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.
Authors: Eleni Tsakiri, Carlos Campos-Marques, Christina Ploumi, Kalliopi Skourti, Antonis Roussos, Eirini Mytilinaiou, Anastasia Vamvaka Iakovou, Ildete Luísa Ferreira, Chrysoula Dioli, Despoina D. Gianniou, Martina Samiotaki, Jonas Campos, Clarissa Waites, Nuno Sousa, Ioannis P. Trougakos, Joana M. Silva, A. Cristina Rego, Ioannis Sotiropoulos, Konstantinos Palikaras
Institutions: National and Kapodistrian University of Athens, University of Minho, National Centre of Scientific Research "Demokritos", Institute of Biosciences & Applications, Centro de Neurociências e Biologia Celular, Centro de Inovação em Biomedicina e Biotecnologia, University of Coimbra, Alexander Fleming Biomedical Sciences Research Center, Columbia University Irving Medical Center, Columbia University, Centro Universitário de Jaguariúna
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Funders: European Commission, Centre National de la Recherche Scientifique, National and Kapodistrian University of Athens, Universidade de Coimbra, Universidade do Minho, Hellenic Foundation for Research and Innovation, National Institutes of Health, Irving Medical Center, Columbia University, Fundação para a Ciência e a Tecnologia, European Regional Development Fund, HORIZON EUROPE European Research Council
Awards: G108378697, G1167214205, G1223021350, G1297482482, G1337233005, G1577006909, G1578237752, G1754748899, G1888088267, G1919449872, Centro de Inovação em Biomedicina e Biotecnologia, G1953887145, G3436757403, Uncovering stress-induced mechanisms of Tau pathology in Alzheimer's disease, G3845165712, G3891694003, G4015828041, G4420342495, G466952628, G4705738886, Lifetime Stress and exosomes in the vulnerability "footprints" of Alzheimer’s disease, G4813068973, G491858407, Decoding mitochondrial selective autophagy in synaptic homeostasis during ageing, G5532215239, Centro de Inovação em Biomedicina e Biotecnologia, G6812757319, G6894495220, Centro de Inovação em Biomedicina e Biotecnologia - Laboratório Associado, G7331859268, G810402943, G8954508221, G9000028377, G9000131804, Caenorhabditis Genetics Center
OpenAlex ID: W7166674869