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

## TL;DR

This study maps how human Tau protein interacts with other proteins over time in fruit flies, revealing that mitochondria and a protein called Porin/VDAC1 play a key role in Tau-related neurodegeneration.

## Contribution

The study provides the first temporal interactome map of human Tau in a living organism and identifies Porin/VDAC1 as a critical modulator of Tau toxicity.

## Key findings

- Human Tau's interactome in Drosophila shifts from cytosolic to mitochondrial associations over time.
- Porin/VDAC1 is a late-stage Tau interactor involved in mitochondrial dysfunction and Tau pathology.
- Reducing Porin levels decreases Tau aggregation but worsens Tau-induced toxicity in flies.

## 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.