The mitochondrial RNA granule modulates manganese-dependent cell toxicity

Area of Science:

• Neurobiology
• Cellular Biology
• Toxicology

Background:

• Prolonged manganese exposure leads to manganism, a neurodegenerative movement disorder.
• Cellular mechanisms underlying manganese toxicity and adaptation are not well understood.
• Genetic models with increased manganese susceptibility, SLC30A10 and PARK2, were utilized.

Purpose of the Study:

• To investigate cellular processes affected by manganese exposure.
• To identify adaptive mechanisms against manganese toxicity.
• To explore the role of mitochondrial RNA granules in manganese neurotoxicity.

Main Methods:

• Studied genetic cellular models (SLC30A10, PARK2) and manganese exposure.
• Analyzed mitochondrial RNA granule composition and function.
• Utilized CRISPR gene editing and pharmacological inhibition.
• Examined adult *Drosophila* mutants.

Main Results:

• Manganese exposure and mutations compromised mitochondrial RNA granule function and disrupted transcript processing.
• RNA granule defects impaired mitochondrial respiratory chain assembly and function.
• Impaired RNA granule function was observed in surviving cells, suggesting an adaptive role.
• CRISPR editing of FASTKD2/DHX30 and pharmacological inhibition were protective against acute manganese toxicity.
• *Drosophila* mutants with *scully* defects showed protection from manganese-induced mortality.

Conclusions:

• Impairment of mitochondrial RNA granule function is a protective mechanism against acute manganese toxicity.
• This adaptive response involves altered RNA processing and mitochondrial function.
• Targeting mitochondrial RNA granules may offer therapeutic strategies for manganese toxicity.