Aggregation prone Tau impairs mitochondrial import, which affects organelle morphology and neuronal complexity.

Mitochondrial protein import is essential for organellar biogenesis, and thereby for the sufficient supply of cytosolic ATP-particularly important for cells with high energy demands like neurons. This study explores the prospect of import machinery perturbation as a cause of neurodegeneration instigated by the accumulation of aggregating proteins linked to disease. The aggregation-prone Tau variant (TauP301L) reduces the levels of components of the import machinery of the outer (TOM20) and inner membrane (TIM23) while associating with TOM40. Intriguingly, this interaction affects mitochondrial morphology, but not protein import or respiratory function; raising the prospect of an intrinsic rescue mechanism. Indeed, TauP301L induced the formation of tunnelling nanotubes (TNTs), potentially for the recruitment of healthy mitochondria from neighbouring cells and/or the disposal of mitochondria incapacitated by aggregated Tau. Consistent with this, inhibition of TNT formation (and rescue) reveals Tau-induced import impairment. In primary neuronal cultures, TauP301L induced morphological changes characteristic of neurodegeneration. Interestingly, these effects were mirrored in cells where the import sites were blocked artificially. Our results reveal a link between aggregation-prone Tau and defective mitochondrial import machinery relevant to disease.