biostudies-literatureCelardo IMedical Research Councile2271https://www.ebi.ac.uk/biostudies/studies/S-EPMC5143399biostudies-literatureUnknown7(6)Mutations in PINK1 and PARKIN cause early-onset Parkinson's disease (PD), thought to be due to mitochondrial toxicity. Here, we show that in Drosophila pink1 and parkin mutants, defective mitochondria also give rise to endoplasmic reticulum (ER) stress signalling, specifically to the activation of the protein kinase R-like endoplasmic reticulum kinase (PERK) branch of the unfolded protein response (UPR). We show that enhanced ER stress signalling in pink1 and parkin mutants is mediated by mitofusin bridges, which occur between defective mitochondria and the ER. Reducing mitofusin contacts with the ER is neuroprotective, through suppression of PERK signalling, while mitochondrial dysfunction remains unchanged. Further, both genetic inhibition of dPerk-dependent ER stress signalling and pharCell death & diseaseMitofusin-mediated ER stress triggers neurodegeneration in pink1/parkin models of Parkinson's disease.PMC5143399MC_U132692719MC_U132674518Costa ACCelardo IMallucci GRMartins LMLehmann SMencacci NELoh SHJones CWood NfalseMitofusin-mediated ER stress triggers neurodegeneration in pink1/parkin models of Parkinson's disease.Mutations in PINK1 and PARKIN cause early-onset Parkinson's disease (PD), thought to be due to mitochondrial toxicity. Here, we show that in Drosophila pink1 and parkin mutants, defective mitochondria also give rise to endoplasmic reticulum (ER) stress signalling, specifically to the activation of the protein kinase R-like endoplasmic reticulum kinase (PERK) branch of the unfolded protein response (UPR). We show that enhanced ER stress signalling in pink1 and parkin mutants is mediated by mitofusin bridges, which occur between defective mitochondria and the ER. Reducing mitofusin contacts with the ER is neuroprotective, through suppression of PERK signalling, while mitochondrial dysfunction remains unchanged. Further, both genetic inhibition of dPerk-dependent ER stress signalling and phar2016-01-01T00:00:00Z2016 Jun2025-04-21T20:27:13.368Z2019-03-27T02:31:02ZS-EPMC51433992733671510.1038/cddis.2016.173