This study investigated how tau regulates mitochondrial reverse electron transport (RET) in fly, mouse, and human iPSC-derived neuron models of tauopathy, examining the mechanistic link between tau pathology and mitochondrial dysfunction.
Tau enters mitochondria and binds the complex I subunit NDUFS3 in a phosphorylation-dependent manner, promoting RET, excess ROS, and a reduced NAD+/NADH ratio. Elevated RET further drives tau hyperphosphorylation, creating a self-reinforcing loop; inhibiting RET reduced tau toxicity across all three species models.
Full text was not available for review — specific quantitative outcomes, effect sizes, and methodological details could not be verified. Findings are based on model systems (flies, mice, iPSC neurons) and have not yet been tested in human clinical trials. Causal directionality in human disease remains to be confirmed.
RET inhibition is a potential new therapeutic strategy for tauopathies; clinicians should watch for emerging agents targeting mitochondrial complex I RET as this mechanistic pathway moves toward translational development.
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