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

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

  • Free Radic Biol Med. 2024 Oct 12:225:665-676. doi: 10.1016/j.freeradbiomed.2024.10.281.
Xiao Han 1,  Bingge Zhang 2,  Qichao Gong 3,  Tiansu Liu 4,  Chao Wang 5,  Yuguo Sun 1,  Hongyi Jia 6,  Yinyan Pu 7,  Qinghua Hou 8,  Xifei Yang 9
Affiliations

Affiliations

  • 1 Department of Toxicology, School of Public Health, Shanxi Medical University, Taiyuan, 030001, Shanxi, China; Shenzhen Key Laboratory of Modern Toxicology, Shenzhen Medical Key Discipline of Health Toxicology (2020-2024), Shenzhen Center for Disease Control and Prevention, Shenzhen, China.
  • 2 Shenzhen Key Laboratory of Modern Toxicology, Shenzhen Medical Key Discipline of Health Toxicology (2020-2024), Shenzhen Center for Disease Control and Prevention, Shenzhen, China.
  • 3 State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, 518055, China.
  • 4 Shenzhen Key Laboratory of Modern Toxicology, Shenzhen Medical Key Discipline of Health Toxicology (2020-2024), Shenzhen Center for Disease Control and Prevention, Shenzhen, China; School of Public Health, Guizhou Medical University, Guizhou, China.
  • 5 Chemical Analysis & Physical Testing Institute, Shenzhen Center for Disease Control and Prevention, Shenzhen, 518055, China.
  • 6 Shenzhen Key Laboratory of Modern Toxicology, Shenzhen Medical Key Discipline of Health Toxicology (2020-2024), Shenzhen Center for Disease Control and Prevention, Shenzhen, China; Jinan University College of Pharmacy, Guangzhou, China.
  • 7 Shenzhen Key Laboratory of Modern Toxicology, Shenzhen Medical Key Discipline of Health Toxicology (2020-2024), Shenzhen Center for Disease Control and Prevention, Shenzhen, China; Department of Preventive Medicine, School of public Health, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China.
  • 8 The Clinical Neuroscience Center, Department of Neurology, The Seventh Affiliated Hospital, Sun Yat-sen University, 518107, China. Electronic address: houqinghua@sysush.com.
  • 9 Department of Toxicology, School of Public Health, Shanxi Medical University, Taiyuan, 030001, Shanxi, China; Shenzhen Key Laboratory of Modern Toxicology, Shenzhen Medical Key Discipline of Health Toxicology (2020-2024), Shenzhen Center for Disease Control and Prevention, Shenzhen, China. Electronic address: xifeiyang@gmail.com.
PMID: 39401732 DOI: 10.1016/j.freeradbiomed.2024.10.281
Abstract

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.

Keywords

Mitophagy; Mn; MnSOD; Oxidative stress; PD; UL.

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