https://www.cell.com/neuron/abstract/S0896-6273(26)00541-6
Sadly this is behind a paywall. I am inclined to the view that there is a role for RET in the deterioration of mitochondrial function that gives rise to ageing. Possibly through the increasing alkalinisation of the matrix.
Highlights
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Mitochondrial RET is activated in fly, mouse, and human iPSC models of tauopathies
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p-tau and pathogenic tau interact with complex I subunit NDUFS3 to promote RET
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RET regulation under stress is a normal physiological function of tau
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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.