Aberrant mitochondrial dynamics disrupts mitochondrial function and contributes to disease conditions. A targeted RNA interference screen for deubiquitinating enzymes (DUBs) affecting protein levels of multifunctional mitochondrial fusion protein Mitofusin (MFN) identified USP8 prominently influencing MFN levels. Genetic and pharmacological inhibition of USP8 normalized the elevated MFN protein levels observed in PINK1 and Parkin-deficient models. This correlated with improved mitochondrial function, locomotor performance and life span, and prevented dopaminergic neurons loss in Drosophila PINK1 KO flies. We identified a novel target antagonizing pathologically elevated MFN levels, mitochondrial dysfunction, and dopaminergic neuron loss of a Drosophila model of mitochondrial dysfunction.his work was supported by grants from the Italian Ministry of Health “Ricerca Finalizzata” (GR-2011-02351151), Rita Levi Montalcini “Brain Gain” program, and Michael J Fox RRIA 2014 (Grant ID 9795) to E Ziviani and by ERC FP7-282280, FP7 CIG PCIG13-GA-2013-618697, and Italian Ministry of Research FIRB RBAP11Z3YA_005 to L Scorrano. AJ Whitworth is funded by MRC Core funding (MC_UU_00015/6)
