Disease-associated tau impairs mitophagy by inhibiting Parkin translocation to mitochondria

Area of Science:

• Neuroscience
• Cell Biology
• Genetics

Background:

• Accumulation of tau protein is a hallmark of Alzheimer's disease (AD) and frontotemporal dementia (FTD).
• Mitochondrial dysfunction is also a key feature of these neurodegenerative diseases.
• The precise impact of tau on mitochondrial quality control, particularly mitophagy, remains largely unknown.

Purpose of the Study:

• To investigate whether disease-associated tau protein directly affects Parkin-dependent mitophagy.
• To elucidate the mechanism by which tau may interfere with the clearance of damaged mitochondria.

Main Methods:

• Utilized the mito-QC mitophagy reporter in neuroblastoma cells.
• Expressed human wild-type (hTau) and FTD mutant tau (hP301L) in cell culture and in *Caenorhabditis elegans*.
• Assessed Parkin translocation to mitochondria and mitochondrial membrane potential.

Main Results:

• Both hTau and hP301L inhibited mitophagy in neuroblastoma cells by reducing Parkin translocation.
• hTau reduced mitophagy in *C. elegans*, while hP301L completely inhibited it.
• Tau impaired Parkin recruitment by sequestering it in the cytosol via aberrant interactions, independent of mitochondrial membrane potential or cytoskeleton integrity.

Conclusions:

• Disease-associated tau inhibits Parkin-dependent mitophagy, a crucial mitochondrial quality control pathway.
• Tau sequesters Parkin, preventing its access to damaged mitochondria.
• This inhibition of mitophagy by tau may contribute to a vicious cycle in neurodegenerative diseases characterized by tauopathy and mitochondrial dysfunction.