Stanford and UCSF researchers discover tau protein infiltrates mitochondria, disrupting energy production in Alzheimer's disease

Stanford and UCSF researchers discovered that hyperphosphorylated tau protein enters mitochondria and binds to the NDUFS3 subunit, forcing electrons to flow backward in a toxic process called reverse electron transport. This retrograde flow impairs ATP production and releases reactive oxygen species, driving a vicious cycle of neuroinflammation. In animal models, the experimental drug CPT successfully blocked this binding, restoring cognitive performance and reducing neurodegeneration.

Tau mitochondrial infiltration mechanism

• ▪Only tau molecules that have undergone specific phosphorylation events are able to enter mitochondria and induce reverse electron transport.
• ▪Stanford Medicine and UCSF researchers discovered that wayward tau molecules can enter mitochondria and disrupt their internal energy-production lines.

NDUFS3 binding disruption

• ▪Genetically or pharmacologically depleting tau in experimental models halted the binding of tau to NDUFS3 and eliminated stress-induced reverse electron transport.
• ▪Phosphorylated tau molecules bind to NDUFS3, a component of the mitochondrial electron-transport chain, warping its shape and causing electrons to flow backward.

Reverse electron transport toxicity

• ▪Reverse electron transport in mitochondria disrupts the conversion of calories from glucose or fat into ATP, the cell's universal energy currency.
• ▪Reverse electron transport is activated under stress and is generally absent or occurring at very low levels in healthy, unstressed cells.

Reactive oxygen species generation

• ▪The massive release of reactive chemicals increases the likelihood of tau hyperphosphorylation, creating a self-perpetuating, vicious cycle of pathology.
• ▪The backward flow of electrons produces large amounts of highly reactive, noxious chemicals, causing inflammation and damage to cellular proteins.

CPT drug therapeutic intervention

• ▪An experimental drug called CPT prevents hyperphosphorylated tau from binding to NDUFS3, blocking reverse electron transport without impairing normal electron flow.
• ▪In tauopathy mouse models, an extended CPT regimen inhibited mitochondrial reverse electron transport, improved cognitive performance, and prevented nerve-cell inflammation.

Tauopathy disease context

• ▪Tauopathies, including Alzheimer's, Parkinson's, and Huntington's diseases, are characterized by deteriorating performance of intracellular mitochondria.
• ▪The newly discovered mitochondrial pathway of tau is entirely independent of both neurofibrillary-tangle formation and microtubule instability.

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