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Article

Temporal Interactome Mapping of Human Tau in Drosophila Reveals Progressive Mitochondrial Engagement and Porin/VDAC1-Dependent Modulation of Toxicity

by
Eleni Tsakiri
1,†,
Martina Samiotaki
2,
Efthimios M. C. Skoulakis
1 and
Katerina Papanikolopoulou
1,*
1
Institute for Fundamental Biomedical Research, Biomedical Sciences Research Centre “Alexander Fleming”, 16672 Athens, Greece
2
Institute for Bio-Innovation, Biomedical Sciences Research Centre “Alexander Fleming”, 16672 Vari, Greece
*
Author to whom correspondence should be addressed.
†
Current address: Department of Physiology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece.
Int. J. Mol. Sci. 2025, 26(19), 9741; https://doi.org/10.3390/ijms26199741
Submission received: 10 August 2025 / Revised: 3 October 2025 / Accepted: 5 October 2025 / Published: 7 October 2025
(This article belongs to the Special Issue Genetic Advances in Neurobiology of Health and Disease)
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Abstract

Tau protein misfolding and aggregation are central to Tauopathies, yet the temporal dynamics of Tau interactions in vivo remain poorly understood. Here, we applied quantitative proteomics to demonstrate that the interactome of human Tau in adult Drosophila brains changes dynamically over a 12-day time course, revealing a progressive shift from early cytosolic and ribosomal associations to late enrichment of mitochondrial and synaptic partners. Notably, the mitochondrial pore protein Porin/VDAC1 was identified as a late-stage interactor and functional analyses demonstrated that Tau overexpression impairs mitochondrial respiration, elevates oxidative damage, and disrupts carbohydrate homeostasis. To validate this temporally specific interaction, Porin was downregulated, resulting in reduced Tau mitochondrial association, phosphorylation and aggregation. Paradoxically, however, Porin attenuation exacerbated Tau-induced toxicity, including shortened lifespan, locomotor deficits, and impaired learning. These findings indicate that while Porin facilitates pathological Tau modifications, it is also essential for neuronal resilience, highlighting a complex role in modulating Tau toxicity. Our study provides a temporal map of Tau-associated proteome changes in vivo and identifies mitochondria as critical mediators of Tau-driven neurodegeneration.
Keywords: Tau protein; Drosophila; proteomics; mitochondria; porin Tau protein; Drosophila; proteomics; mitochondria; porin

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MDPI and ACS Style

Tsakiri, E.; Samiotaki, M.; Skoulakis, E.M.C.; Papanikolopoulou, K. Temporal Interactome Mapping of Human Tau in Drosophila Reveals Progressive Mitochondrial Engagement and Porin/VDAC1-Dependent Modulation of Toxicity. Int. J. Mol. Sci. 2025, 26, 9741. https://doi.org/10.3390/ijms26199741

AMA Style

Tsakiri E, Samiotaki M, Skoulakis EMC, Papanikolopoulou K. Temporal Interactome Mapping of Human Tau in Drosophila Reveals Progressive Mitochondrial Engagement and Porin/VDAC1-Dependent Modulation of Toxicity. International Journal of Molecular Sciences. 2025; 26(19):9741. https://doi.org/10.3390/ijms26199741

Chicago/Turabian Style

Tsakiri, Eleni, Martina Samiotaki, Efthimios M. C. Skoulakis, and Katerina Papanikolopoulou. 2025. "Temporal Interactome Mapping of Human Tau in Drosophila Reveals Progressive Mitochondrial Engagement and Porin/VDAC1-Dependent Modulation of Toxicity" International Journal of Molecular Sciences 26, no. 19: 9741. https://doi.org/10.3390/ijms26199741

APA Style

Tsakiri, E., Samiotaki, M., Skoulakis, E. M. C., & Papanikolopoulou, K. (2025). Temporal Interactome Mapping of Human Tau in Drosophila Reveals Progressive Mitochondrial Engagement and Porin/VDAC1-Dependent Modulation of Toxicity. International Journal of Molecular Sciences, 26(19), 9741. https://doi.org/10.3390/ijms26199741

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