2026-08-06 スタンフォード大学
＜関連情報＞
- https://news.stanford.edu/stories/2026/08/tau-alzheimers-nerve-cells-research-neurodegenerative-disorders
- https://www.cell.com/neuron/abstract/S0896-6273(26)00541-6
タウタンパク質によって誘発されるミトコンドリア逆電子伝達が神経変性を引き起こす Tau-induced mitochondrial reverse electron transport drives neurodegeneration
Wen Li ∙ Suman Rimal ∙ Sunil Bhurtel ∙ … ∙ William W. Seeley ∙ Su Guo ∙ Bingwei Lu
Neuron Published:August 6, 2026
DOI:https://doi.org/10.1016/j.neuron.2026.07.012
Highlights
- Mitochondrial RET is activated in fly, mouse, and human iPSC models of tauopathies
- p-tau and pathogenic tau interact with complex I subunit NDUFS3 to promote RET
- RET regulation under stress is a normal physiological function of tau
- Pharmacological inhibition of RET protects against tauopathy across species
Summary
Hyperphosphorylation and aggregation of tau are pathological hallmarks of tauopathies. Mitochondrial dysfunction is also a common feature of tauopathies. The mechanistic link between tau abnormalities and mitochondrial dysfunction and its relationship to the physiological function of tau, however, is unclear. Here, we demonstrate that tau regulates mitochondrial reverse electron transport (RET), which produces excess reactive oxygen species (ROS), reduces the NAD+/NADH ratio, and is activated by aging or stress. In flies, mice, and human induced pluripotent stem cell (hiPSC)-derived neurons, tau depletion eliminates stress-induced RET and confers resilience. Mechanistically, tau enters mitochondria and directly interacts with the complex I subunit NDUFS3 to promote RET in a phosphorylation-dependent manner. Elevated RET further drives tau hyperphosphorylation, establishing a self-perpetuating pathological loop. Inhibition of RET ameliorates tau toxicity across species. RET regulation thus represents a previously unrecognized normal function of tau that becomes pathological in disease, providing a therapeutic target for various conditions characterized by tau abnormalities and mitochondrial dysfunction.
