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

Manganese (Mn²⁺) is among the indispensable trace elements required by the human body, but high-dose Mn²⁺ exposure can lead to Mn poisoning. Therefore, the tolerable upper intake level (UL) for Mn²⁺ has been established for normal individuals in different countries. However, whether the UL of Mn²⁺ is suitable for the patients of Parkinson's disease (PD) is unclear.

Here, we found unexpectedly that the dietary UL of Mn²⁺ supplement enhanced mitophagy through the PINK1/Parkin-mediated ubiquitin-dependent pathway in MPTP- induced mice and cells. Mn²⁺ promoted mitochondrial biogenesis and dynamics, thereby increased the activity of the mitochondrial respiratory chain with restored mitochondrial function. Additionally, Mn²⁺ 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 Mn²⁺.

These findings demonstrate that the dietary UL of Mn²⁺ 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 Mn²⁺ intake.