Mitochondrial protein import stress causes progressive neurodegeneration opposed by PERK - eIF2α signalling

Authors

Ebding, J., Barth, M., Lion, L. M., Gackstatter, A., Link, S., Pirritano, M., Gasparoni, G., Simon, M., Herrmann, J., Pielage, J.

Abstract

Mitochondrial dysfunction and impairments of the mitochondrial protein import system are often linked to neurodegenerative disease, but whether import stress per se causes neurodegeneration has not been tested. Here, we adapted the yeast clogger system to Drosophila motoneurons to block TOM-TIM23-mediated import with temporal control. Sustained import stress converts somatic mitochondria into donut-shaped structures, depletes functional mitochondria from synaptic terminals, and causes progressive neurodegeneration with impaired neurotransmitter release and locomotor dysfunction. This neurodegeneration is mechanistically distinct from mitochondrial absence, as miro mutant neurons that completely lack presynaptic mitochondria do not degenerate. Import-stressed motoneurons activate multiple protective programmes, including chaperone remodelling, metabolic repression, and translational control through the eIF2 kinase PERK. Both pharmacological PERK inhibition and reversal of translational attenuation via ISRIB accelerate neurodegeneration, whereas PERK overexpression alone is sufficient to cause it, defining a protective range of eIF2-dependent translational control. The observation that PERK inhibition is protective in protein misfolding models but detrimental during import stress shows that the nature of mitochondrial dysfunction determines the molecular consequence of translational control in neurodegeneration.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 15 Apr 2026.

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