Tau Protein Disrupts Mitochondrial Homeostasis in a Yeast Model: Implications for Alzheimer’s Disease

Abstract

The microtubule-associated protein tau plays a central role in neurodegenerative diseases, called tauopathies, but the mechanism involved remains incompletely understood. Here, we used Saccharomyces cerevisiae as a model system to investigate the consequences of expressing the shortest human tau isoform 0N3R. After transfected, we detected widespread cellular distribution of tau and phosphorylation at key pathological residues involved in Alzheimer’s disease (Ser199/202). We also found that a portion of tau localizes within the mitochondrial matrix. The mitochondrial uptake of tau required a chaperone machinery, including Hsp104 and the Ssa1/Ydj1 bichaperone complex. Functionally, tau expression caused marked mitochondrial fragmentation, reduced oxygen consumption, and a decrease in membrane potential during stationary phase, indicating impaired mitochondrial function. This dysfunction activated the yeast retrograde signaling pathway. Importantly, tau expression enhanced mitochondrial clearance through mitophagy, both under nitrogen starvation and during stationary phase, and this effect was dependent on the retrograde response. Together, these findings demonstrate that tau expression in yeast perturbs mitochondrial homeostasis, triggering both compensatory nuclear signaling and increased mitochondrial turnover, adding evidence on the potential mechanisms involved in tau neurotoxicity. Graphical Abstract

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