Ret rescues mitochondrial morphology and muscle degeneration of Drosophila Pink1 mutants

Parkinson's disease (PD)‐associated Pink1 and Parkin proteins are believed to function in a common pathway controlling mitochondrial clearance and trafficking. Glial cell line‐derived neurotrophic factor (GDNF) and its signaling receptor Ret are neuroprotective in toxin‐based animal models of PD. However, the mechanism by which GDNF/Ret protects cells from degenerating remains unclear. We investigated whether the Drosophila homolog of Ret can rescue Pink1 and park mutant phenotypes. We report that a signaling active version of Ret ( Ret MEN 2B ) rescues muscle degeneration, disintegration of mitochondria and ATP content of Pink1 mutants. Interestingly, corresponding phenotypes of park mutants were not rescued, suggesting that the phenotypes of Pink1 and park mutants have partially different origins. In human neuroblastoma cells, GDNF treatment rescues morphological defects of PINK1 knockdown, without inducing mitophagy or Parkin recruitment. GDNF also rescues bioenergetic deficits of PINK knockdown cells. Furthermore, overexpression of Ret MEN 2B significantly improves electron transport chain complex I function in Pink1 mutant Drosophila . These results provide a novel mechanism underlying Ret‐mediated cell protection in a situation relevant for human PD. Synopsis Glial cell line derived neurotrophic factor (GDNF) improves survival in toxin‐models of Parkinson's disease and is currently undergoing clinical development, however the protective mechanism is elusive. This study provides evidence that the GDNF receptor Ret rescues defects of a genetic Parkinson model and proposes a new mechanism‐of‐action. Active Ret overexpression rescues muscle degeneration and mitochondrial morphology in muscles and dopamine neurons in Pink1 mutant Drosophila. In human neuroblastoma cells, GDNF treatment rescues mitochondrial fragmentation caused by Pink1 knockdown. Ret signaling improves mitochondrial respiration and activity of complex I, providing a potential novel mechanism for the protective effect of GDNF/Ret. Graphical Abstract A fly model for Parkinson's Disease shows that the neurotrophic factor GDNF and its receptor Ret rescue disease‐associated defects by affecting the mitochondrial electron chain function, revealing the basis of GDNF's therapeutic promise.