The tolerable upper intake level of manganese alleviates Parkinson-like motor performance and neuronal loss by activating mitophagy.

Manganese (Mn) is among the indispensable trace elements required by the human body, but high-dose Mn exposure can lead to Mn poisoning. Therefore, the tolerable upper intake level (UL) for Mn has been established for normal individuals in different countries. However, whether the UL of Mn is suitable for the patients of Parkinson's disease (PD) is unclear. Here, we found unexpectedly that the dietary UL of Mn supplement enhanced mitophagy through the PINK1/Parkin-mediated ubiquitin-dependent pathway in MPTP- induced mice and cells. Mn promoted mitochondrial biogenesis and dynamics, thereby increased the activity of the mitochondrial respiratory chain with restored mitochondrial function. Additionally, Mn directly elevated the activity of mitochondrial superoxide dismutase (MnSOD), which contributed to the clearance of reactive oxygen species (ROS), restored dopaminergic and motor functions in the MPTP-induced PD mouse model. Similar results were also observed in SH-SY5Y cells, whereas knockdown parkin using siRNA or application of mitophagy inhibitors (Mdivi-1 or Cyclosporine A), abolished the neuroprotective effects of Mn. These findings demonstrate that the dietary UL of Mn is protective for the MPTP-induced Parkinson-like lesions with the mechanisms involving the activation of mitophagy, suggesting potential intervention of PD by moderately increasing dietary Mn intake.