Tau protein as a regulator of mitochondrial function and dynamics
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
- Antonis Roussos
- Despoina D. Gianniou (ORCID: https://orcid.org/0000-0002-8111-6528)
- Ioannis Sotiropoulos (ORCID: https://orcid.org/0000-0003-0115-0038)
- Konstantinos Palikaras (ORCID: https://orcid.org/0000-0001-6992-5560)
- Ioannis P. Trougakos (ORCID: https://orcid.org/0000-0002-6179-2772)
- A. Cristina Rego (ORCID: https://orcid.org/0000-0003-0700-3776)
- Nuno Sousa (ORCID: https://orcid.org/0000-0002-8755-5126)
- Ildete L. Ferreira (ORCID: https://orcid.org/0000-0001-6552-4479)
- Chrysoula Dioli (ORCID: https://orcid.org/0000-0002-2387-0258)
- Joana Silva (ORCID: https://orcid.org/0000-0002-8257-3413)
- Christina Ploumi (ORCID: https://orcid.org/0000-0002-2389-5471)
- Jonas Campos (ORCID: https://orcid.org/0000-0001-8487-6621)
- Martina Samiotaki (ORCID: https://orcid.org/0000-0001-9952-0636)
- Eirini Mytilinaiou
- Carlos Campos‐Marques (ORCID: https://orcid.org/0000-0002-0612-4333)
- Kalliopi Skourti
- Eleni Tsakiri
- Clarissa Waites
- Anastasia Vamvaka Iakovou (ORCID: https://orcid.org/0000-0003-2031-9337)
Institutions
- Max Planck Society (DE)
- National and Kapodistrian University of Athens (GR)
- National Centre of Scientific Research "Demokritos" (GR)
- Institute for Biomedicine (IT)
- Institute on Aging (US)
- Alexander Fleming Biomedical Sciences Research Center (GR)
- University of Coimbra (PT)
- Columbia University (US)
- University of Minho (PT)
Publication Details
- Journal
- Proceedings of the National Academy of Sciences
- Published
- 2026-06-30
- DOI
- https://doi.org/10.1073/pnas.2521642123
- Primary Topic
- Mitochondrial Function and Pathology
- Type
- article
- Field-Weighted Citation Impact
- 0.00
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