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

Area of Science:

• Neuroscience
• Cell Biology
• Biochemistry

Background:

• The microtubule-associated protein tau is implicated in neurodegenerative tauopathies.
• Mechanisms underlying tau's role in disease pathogenesis require further elucidation.

Purpose of the Study:

• To investigate the cellular consequences of expressing the shortest human tau isoform (0N3R) in Saccharomyces cerevisiae.
• To explore tau's impact on mitochondrial function and cellular responses.

Main Methods:

• Transfection of yeast with the shortest human tau isoform (0N3R).
• Analysis of tau localization, phosphorylation, and mitochondrial morphology.
• Assessment of mitochondrial function, oxygen consumption, and membrane potential.
• Investigation of the retrograde signaling pathway and mitophagy.

Main Results:

• Tau distributed widely in yeast cells, with pathological phosphorylation at Alzheimer's disease-related residues.
• A portion of tau localized to the mitochondrial matrix, facilitated by chaperone machinery.
• Tau expression induced mitochondrial fragmentation, reduced oxygen consumption, and decreased membrane potential.
• Mitochondrial dysfunction activated the yeast retrograde signaling pathway, enhancing mitophagy.

Conclusions:

• Tau expression perturbs mitochondrial homeostasis in yeast.
• Tau triggers compensatory nuclear signaling and increased mitochondrial turnover (mitophagy).
• Findings provide insights into potential mechanisms of tau neurotoxicity.