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Published on: July 12, 2012
Role of brain lysosomes in the development of manganese toxicity in mice
Abstract:
To study the mechanism of development of manganese toxicity, the manganese content in blood, brain, liver, and subcellular fractions of brain was measured at several intervals following ip injection of a single dose of manganese (245 mg Mn(CH3COO)2 X 4H2O/kg body wt) in mice. The ultrastructural alterations in neurons were correlated with the data for manganese content. Peak concentrations of manganese in blood and liver occurred and disappeared in less than 24 hr. In brain, however, manganese concentration was maintained for 4 days and decreased very little during the 10-day postdose interval studied. Most of the absorbed manganese in brain was recovered in mitochondria and lysosome-rich fractions separated by density gradient centrifugation. Lysosomes took up manganese to a greater extent than mitochondria when compared to controls. Electron microscopy revealed that by 24-hr postdose the number of lysosomes in neurons increased in corpus striatum and midbrain in mice given manganese by ip injection. These results suggested that brain lysosomes play an important role in the cellular metabolism of manganese and in the development of manganese toxicity.
Insights
Manganese accumulates in mouse brain lysosomes for days after exposure, contributing to toxicity. This suggests brain lysosomes are key to cellular manganese metabolism and toxic effects.
Area of Science:
- Neuroscience
- Toxicology
- Cell Biology
Background:
- Manganese is an essential element, but excess exposure can lead to neurotoxicity.
- The precise mechanisms underlying manganese-induced neurotoxicity are not fully understood.
- Investigating cellular targets and accumulation patterns is crucial for understanding manganese toxicity.
Purpose of the Study:
- To elucidate the mechanism of manganese toxicity development.
- To correlate manganese content in various tissues and cellular fractions with ultrastructural changes in neurons.
- To identify the role of specific brain cellular components in manganese accumulation and toxicity.
Main Methods:
- Mice were administered a single dose of manganese acetate.
- Manganese levels were measured in blood, brain, liver, and brain subcellular fractions over 10 days.
- Ultrastructural alterations in neurons were examined using electron microscopy.
- Subcellular fractions were isolated using density gradient centrifugation.
Main Results:
- Manganese concentrations peaked rapidly in blood and liver but remained elevated in the brain for at least 4 days.
- The majority of brain manganese was found in mitochondrial and lysosome-rich fractions.
- Lysosomes showed a greater uptake of manganese compared to mitochondria.
- Electron microscopy revealed an increase in neuronal lysosomes in specific brain regions (corpus striatum, midbrain) 24 hours post-manganese injection.
Conclusions:
- Brain lysosomes play a significant role in the cellular metabolism of manganese.
- Lysosomal accumulation of manganese is implicated in the development of manganese toxicity.
- Understanding lysosomal involvement provides insight into neurotoxic mechanisms of manganese.
