Link to bioRxiv paper:
http://biorxiv.org/cgi/content/short/2022.11.30.518502v1?rss=1

Authors: Needs, H. I., Henley, J., Collinson, I.

Abstract:
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 ready supply of ATP to the cell. The consequences of reduced bioenergetic function are particularly severe for cells with high energetic demands such as neurons. However, relatively little is known about howdefectiveimportcontributestoneurodegeneration, or how neurotoxic proteins characteristic ofneurodegenerative diseases impact mitochondrial import efficiency. Here, we used HeLa cells to investigate how expressing high levels of Tau variants affect mitochondrial import activity, morphology, and function. We found that the variant associated with neurodegeneration (TauP301L) colocalises with mitochondria. TauP301L, but not wildtype Tau, interacts with TOM40, the protein-channel component of the outer membrane protein import complex. Interestingly, TauP301L expression had no discernible effect on overall mitochondrial import function, despite associating with TOM40 and altering mitochondrial morphology, suggesting that a rescue mechanism is at play. This rescue could be explained by the appearance of microtubule and actin containing tunnelling nanotubes (TNTs), used to recruit healthy mitochondria from neighbouring cells and/or dispose of mitochondria with aggregated Tau. Furthermore, in primary neuronal cultures TauP301L induces morphological changes that resemble a neurodegeneration like phenotype, and this is 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, and the mitochondrial protein import machinery relevant to neurodegenerative disease.

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