Mitochondrially Transcribed dsRNA Mediates Manganese-induced Neuroinflammation

Area of Science:

• Neuroscience
• Toxicology
• Molecular Biology

Background:

• Manganese (Mn) is essential but toxic at high levels, causing neurotoxicity.
• Mechanisms of Mn neurotoxicity, including astrogliosis, neuronal loss, and neuroinflammation, are not fully understood.

Purpose of the Study:

• To elucidate a novel Mn-dependent mechanism linking mitochondrial dysfunction to neuroinflammation.
• To identify molecular pathways involved in Mn-induced brain damage.

Main Methods:

• Investigated Mn effects on mitochondrial transcriptome processing in human cerebral organoids.
• Analyzed dsRNA accumulation and its role in activating cytosolic sensor pathways.
• Examined Mn-induced inflammatory responses in vivo using a mouse model (SLC30A10 mutation).

Main Results:

• Manganese disrupts mitochondrial RNA processing, leading to cytoplasmic accumulation of double-stranded RNA (dsRNA).
• This dsRNA activates type I interferon responses and inflammatory cytokine production, primarily in mature astrocytes.
• Similar inflammatory effects were observed in a mouse model of Mn accumulation.

Conclusions:

• Mitochondrial dsRNA is a key mediator of Mn-induced neuroinflammation.
• This pathway provides new insights into the molecular basis of manganism and neurodegenerative diseases.
• The findings suggest potential therapeutic targets for Mn-related neurological disorders.