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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