Perturbation of the mitochondrial import machinery by aggregation prone Tau affects organelle morphology and reduces neuronal complexity

Protein import into mitochondria is an intricate and highly conserved process essential for organellar biogenesis, and maintenance of its structure and function. Defects in the import apparatus impact the assembly of the respiratory chain and ATP synthase complexes required for oxidative phosphorylation, compromising the supply of ATP to the cytosol. The consequences of reduced bioenergetic function are particularly severe for cells with high energetic demands, such as neurons. However, relatively little is known about how defective import contributes to neurodegeneration, or how aggregation prone toxic proteins, characteristic of neurodegenerative disease, impact mitochondrial import efficiency. Here, we used HeLa cells to investigate how expressing Tau, or a disease-causing variant, affects mitochondrial import activity, morphology, and function. We found that a variant associated with frontotemporal dementia (Tau P301L ), but not the native version, colocalises with mitochondria, associating with TOM40–the protein-channel component of the outer membrane import complex. Interestingly, Tau P301L production had no discernible effect on overall mitochondrial import function, despite associating with TOM40 and altering mitochondrial morphology. This raised suspicions of a rescue mechanism manifested by the appearance of microtubule and actin containing tunnelling nanotubes (TNTs), used to recruit healthy mitochondria from neighbouring cells and/ or dispose of mitochondria containing aggregated Tau. Furthermore, in primary neuronal cultures Tau P301L induces morphological changes that resemble a neurodegeneration-like phenotype–also mirrored in cells where the import sites are blocked artificially. These results reveal an intriguing link between the production of aggregation prone protein variants, such as Tau P301L and others, with the mitochondrial protein import machinery relevant to neurodegenerative disease.