Tau-induced mitochondrial reverse electron transport drives neurodegeneration, 2026, Li et al.

[Chandelier]

Tau-induced mitochondrial reverse electron transport drives neurodegeneration

Spoiler: Authors

Li, Wen; Rimal, Suman; Bhurtel, Sunil; Yeung, Lucas; Lu, Benjamin G.; Grinberg, Lea T.; Spina, Salvatore; Sillero, Maria Inmaculada Cobos; Seeley, William W.; Guo, Su; Lu, Bingwei

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.

Graphical abstract​

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[Chandelier]

https://www.science.org/content/article/tau-protein-can-sneak-brain-cells-energy-factories-and-wreak-havoc

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In every species Lu and his colleagues studied, they found that p-tau triggers reverse electron transport.​

That suggests it serves an important evolutionary purpose, says Russell Swerdlow, a neurologist at the University of Kansas Medical Center.​

Although reverse electron transport is generally harmful, it may help neurons survive temporary stress.​

Swerdlow says p-tau may be the “toggle switch” that allows cells to switch between energy production and other functions.​

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But an abundance of p-tau may upset that balance.​

Lu’s group found that reverse electron transport triggers pathways that add even more phosphate groups to tau, creating what Lu describes as a “vicious cycle” that in some cases might “run out of control and lead to pathology.”​

It’s not clear what starts the cycle, although Lu suspects wear and tear on enzymes in the aging brain could allow harmful byproducts to build up over time.​

The findings could help explain why people with Alzheimer’s begin to have problems metabolizing glucose long before tau tangles appear, Kosik says.​

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