The Protein That Invades The Brain's Powerhouses and May Accelerate Alzheimer's

A protein essential to neurons can turn into a dangerous invader of mitochondria. Scientists have discovered that the tau protein can trigger a cycle of damage within nerve cells, helping to explain how the brain enters a spiral of degeneration in Alzheimer's disease. The discovery also points to a new target in the search for treatments.

Alzheimer's disease is frequently associated with the accumulation of abnormal proteins in the brain. One of these is the tau protein, which normally performs important functions within neurons, helping to maintain their structure and organize the transport of materials inside them.

The problem begins when this protein undergoes abnormal chemical changes, particularly a process known as excessive phosphorylation. In this state, tau can detach from its normal functions, accumulate, and form toxic structures.

Now, a new study suggests it may also play a surprising and dangerous role: invading mitochondria, the tiny structures responsible for energy production in cells, and triggering a cycle of damage that could contribute to the progression of Alzheimer’s and other brain diseases.

To investigate this relationship, scientists studied more than just one type of organism. They used flies, mice, and human neurons generated in the laboratory from stem cells. This strategy allowed them to determine whether the observed phenomenon was species-specific or if it might represent a broader biological mechanism.

In the experiments involving human cells, researchers started with cells capable of transforming into various cell types and stimulated them to develop into neurons. This enabled them to directly observe how changes associated with the tau protein affect human nerve cells.

The investigation focused primarily on mitochondria. To function, these structures generate energy via a type of electron transport chain. Normally, electrons travel along this chain in a specific direction, helping the cell produce energy. However, researchers discovered that a phenomenon known as reverse electron transport can occur during aging or under stress.

As the name implies, in this process, some electrons move in the opposite direction. This can increase the production of highly reactive molecules known as reactive oxygen species, which are capable of damaging proteins, membranes, and other vital cellular structures.

The most surprising discovery was that the tau protein appears to play a direct role in this process. Scientists observed that, when cells were under stress, tau could enter the mitochondria and interact with a specific protein located within a key energy-production system.

When tau was altered in a manner similar to that observed in neurodegenerative diseases, this interaction became particularly problematic. It promoted reverse electron transport and increased the production of potentially harmful molecules.

To confirm the importance of tau, the researchers also studied organisms and cells in which this protein had been reduced or removed. Under these conditions, stress-induced reverse transport virtually disappeared, and the cells proved to be more resilient.

But the problem did not end there. The results suggest the existence of a vicious cycle. Altered tau enters the mitochondria and increases reverse electron transport. This process generates further stress within the cell. In turn, this stressful environment appears to further promote abnormal changes in the tau protein itself.

In other words, altered tau damages the mitochondria, and the damaged mitochondria can contribute to even more tau becoming abnormal. Over time, this cycle can increase neuronal damage and help explain why diseases like Alzheimer's continue to progress over the years.

One of the most promising aspects of the study was the testing of strategies capable of halting this process. Researchers used substances to reduce or block reverse electron transport and observed a reduction in the toxic effects associated with the tau protein across the various models studied. However, this does not yet mean a new treatment is ready for people with Alzheimer's.

The results were obtained primarily in experimental models, and much more research will be required before a similar strategy can be used clinically. Even so, the discovery opens up a new possibility: it may be possible to protect neurons not only by attempting to eliminate abnormal tau but also by preventing it from turning mitochondria into a continuous source of cellular stress and damage.

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Tau-induced mitochondrial reverse electron transport drives neurodegeneration

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

Neuron. August 06, 2026

DOI:10.1016/j.neuron.2026.07.012

Abstract: 

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.