Tau triggers mitochondrial reverse electron transport

Phosphorylated tau triggered reverse electron transport in mitochondria in models of brain disease

On 6 August, researchers from Stanford and UCSF published a study in Neuron on tau, a protein found in nerve cells. They traced its connection to the mitochondrial electron transport chain in fruit flies, mice, postmortem brain tissue, and human neurons derived from reprogrammed cells. The experimental compound CPT weakened this process in cellular and animal models.

Tau helps maintain the internal structural fibers of neurons. In Alzheimer’s disease and other tauopathies, phosphate groups attach to tau, and the protein forms tangles. The article in Neuron describes another mechanism of damage: some tau carrying these phosphate groups enters mitochondria and binds to NDUFS3, a component of complex I, the first unit in the mitochondrial electron transport chain.

Electrons normally move through this chain in one direction. The energy released by their movement helps mitochondria produce ATP, the molecule that supplies energy to the cell. When tau bound to NDUFS3, some electrons moved in the opposite direction. This reverse flow increased reactive oxygen species, which can damage cellular structures, and altered the ratio of NAD+ to NADH, two molecules that carry electrons within the cell.

These changes added new phosphate groups to tau. The protein then increased reverse electron transport again, completing the feedback loop.

The authors tested each link in this sequence separately. Mutations that prevented tau from binding to NDUFS3 reduced reverse electron transport. Reducing the amount of tau, partially suppressing NDUFS3, and blocking tau from entering mitochondria produced the same effect. In postmortem brain tissue from people with Alzheimer’s disease and progressive supranuclear palsy, another disorder associated with abnormal tau, the researchers also found more interactions between phosphorylated tau and NDUFS3.

The authors conducted a separate experiment in rTg4510 mice. These animals carry the human P301L tau variant and reproduce some of the memory deficits and neurodegeneration associated with tau disease. CPT is an experimental compound that prevents tau from binding to NDUFS3. Mice treated with CPT performed better in tests of memory and behavior. MRI showed a thicker cortex and a larger hippocampal volume, while tissue analysis found fewer signs of inflammation and neurodegeneration. In human neurons carrying mutant tau, CPT reduced vulnerability to oxidative stress.