Summary: Researchers have identified a new, toxic pathway by which tau protein promotes Alzheimer’s disease and related tauopathies. The team found that hyperphosphorylated tau can enter neuronal mitochondria and bind directly to a core electron transport chain subunit, NDUFS3. This interaction distorts NDUFS3’s structure, jams electron flow and forces electrons to move in reverse — a process called reverse electron transport (RET) — which produces excessive reactive oxygen species (ROS), drives inflammation and damages cells independent of neurofibrillary tangle formation or microtubule instability.
Key Facts
- New pathological mechanism: Tau can drive neurodegeneration by disrupting mitochondrial energy production directly, distinct from its roles in forming neurofibrillary tangles or destabilizing microtubules.
- NDUFS3 binding and RET: Hyperphosphorylated tau enters mitochondria and binds the complex I subunit NDUFS3, warping its conformation and triggering reverse electron transport.
- Self-amplifying inflammatory loop: RET generates large amounts of ROS that accelerate tau hyperphosphorylation, creating a damaging cycle of oxidative stress and inflammation.
- Therapeutic rescue with CPT: The experimental compound CPT prevents hyperphosphorylated tau from binding NDUFS3, blocking RET while sparing normal forward electron flow and baseline ATP production.
- Cross-species relevance: CPT treatment preserved brain volume, reduced neuroinflammation and improved cognition in animal tauopathy models and protected human stem cell–derived neurons carrying pathogenic tau mutations.
Source: Stanford
Overview
Tau is a microtubule-associated protein long implicated in Alzheimer’s disease — the leading cause of dementia — and a group of related disorders known as tauopathies. Elevated levels of specific tau species in cerebrospinal fluid or blood reliably predict cognitive decline, and postmortem and imaging studies commonly reveal intracellular neurofibrillary tangles composed largely of aggregated tau. In healthy neurons, tau also helps stabilize microtubules, which are essential for intracellular transport and cell structure.
Although tau aggregation and hyperphosphorylation are established hallmarks of disease, the link between tau abnormalities and mitochondrial dysfunction—common across tauopathies—was not clear. In a study published online Aug. 6 in Neuron, researchers at Stanford Medicine show that hyperphosphorylated tau can enter mitochondria and directly interfere with the electron transport chain, provoking RET and initiating a damaging cascade within mitochondria and neurons.
Lead authors Wen Li, Suman Rimal and colleagues, with senior author Bingwei Lu, PhD, established this mechanism through experiments spanning fruit flies, mice, human brain tissue and human induced pluripotent stem cell (hiPSC)-derived neurons that carry tau mutations found in patients.
How tau disrupts mitochondrial energy production
Mitochondria generate ATP through an electron transport chain in which electrons move sequentially through complexes to drive ATP synthesis. The study demonstrates that only hyperphosphorylated tau can enter mitochondria, where it binds NDUFS3, a core subunit of complex I. This binding distorts complex I, causing electrons to drop from their normal path and flow in reverse — RET — which produces large amounts of ROS and damages proteins, lipids and DNA.
RET is typically minimal under healthy conditions. The authors show that stress or aging can activate RET, and that tau is both an upstream trigger and a downstream amplifier: RET-generated ROS further promote tau hyperphosphorylation, creating a self-perpetuating pathogenic loop.
Experimental validation and therapeutic implications
Across models, reducing tau genetically or blocking its mitochondrial interaction prevented stress-induced RET and conferred resilience. An experimental molecule, CPT, selectively blocked hyperphosphorylated tau’s binding to NDUFS3 and stopped RET while preserving normal forward electron transport and basal ATP levels.
In fly and mouse models, CPT treatment rescued behavioral deficits, reduced neuroinflammation and mitigated neurodegeneration, including preserved cortical thickness and overall brain volume. In hiPSC-derived human neurons carrying pathogenic tau mutations, CPT reduced stress-induced cellular abnormalities. Animals lacking tau were likewise protected from stress-induced deficits and lived longer under certain stress paradigms.
Breaking the vicious cycle
The authors emphasize that RET creates a vicious circle: RET-driven ROS promotes further tau hyperphosphorylation, which in turn enhances mitochondrial RET. Interrupting this cycle by preventing tau’s interaction with complex I or otherwise inhibiting RET offers a promising therapeutic strategy for tauopathies and possibly other conditions that feature abnormal tau phosphorylation and mitochondrial dysfunction, such as traumatic brain injury or stroke.
While CPT shows encouraging preclinical results, the researchers note that further development and testing are required before clinical trials can begin. Bingwei Lu is a co-founder and advisory board member of Cerapeut, Inc., a company developing CPT for neurodegenerative disease.
Funding: This work was supported by the National Institutes of Health (grants R21AG083863, R01NS084412, R01AG089752, R37NS083417 and R01NS120219).
Key Questions Answered:
A: It reveals a distinct, direct mechanism: individual hyperphosphorylated tau molecules infiltrate mitochondria and alter energy-producing complexes to impair cellular metabolism, independently of tau aggregation or microtubule destabilization.
A: Reverse electron transport occurs when the normal directional flow of electrons in the mitochondrial respiratory chain is reversed. RET produces high levels of reactive oxygen species that damage cellular components, trigger inflammation and promote additional tau hyperphosphorylation.
A: CPT prevents hyperphosphorylated tau from binding NDUFS3 and thereby halts RET and its downstream damage, without disrupting normal mitochondrial electron flow or baseline ATP generation in preclinical models.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- The journal paper was reviewed in full.
- Additional context was added by staff to clarify methods and implications.
About this Alzheimer’s disease research news
Author: Mandy Erickson
Source: Stanford
Contact: Mandy Erickson – Stanford
Image: The image is credited to Neuroscience News
Original Research: Open access. “Tau-induced mitochondrial reverse electron transport drives neurodegeneration” by 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, Bingwei Lu. Neuron. DOI: 10.1016/j.neuron.2026.07.012
Abstract
Tau-induced mitochondrial reverse electron transport drives neurodegeneration
Hyperphosphorylation and aggregation of tau are pathological hallmarks of tauopathies, and mitochondrial dysfunction is commonly observed in these disorders. This study demonstrates that tau regulates mitochondrial reverse electron transport (RET), which elevates reactive oxygen species (ROS), lowers the NAD+/NADH ratio and is activated by aging or cellular stress. In flies, mice and hiPSC-derived human neurons, tau depletion prevents stress-induced RET and confers resilience. Mechanistically, phosphorylated tau enters mitochondria and binds the complex I subunit NDUFS3 to promote RET in a phosphorylation-dependent manner. Elevated RET further drives tau hyperphosphorylation, establishing a self-sustaining pathological loop. Inhibition of RET alleviates tau toxicity across species, indicating RET regulation is a previously unrecognized function of tau that becomes pathological in disease and represents a potential therapeutic target for conditions characterized by tau abnormalities and mitochondrial dysfunction.