Abstract
Manganese (Mn) is an essential trace element required for various biological functions, but excessive Mn levels are neurotoxic and lead to significant health concerns. The mechanisms underlying Mn-induced neurotoxicity remain poorly understood. Neuropathological studies of affected brain regions reveal astrogliosis, and neuronal loss, along with evidence of neuroinflammation. Here, we present a novel Mn-dependent mechanism linking mitochondrial dysfunction to neuroinflammation. We found that Mn disrupts mitochondrial transcriptome processing, resulting in the accumulation of complementary RNAs that form double-stranded RNA (dsRNA). This dsRNA is released to the cytoplasm, where it activates cytosolic sensor pathways, triggering type I interferon responses and inflammatory cytokine production. This mechanism is present in 100-day human cerebral organoids, where Mn-induced inflammatory responses are observed predominantly in mature astrocytes. Similar effects were observed in vivo in a mouse model carrying mutations in the SLC30A10 gene, which results in Mn accumulation. These findings highlight a previously unrecognized role for mitochondrial dsRNA in Mn-induced neuroinflammation and provide insights into the molecular basis of manganism. We propose that this mitochondrial dsRNA-induced inflammatory pathway has broad implications in for neurodegenerative diseases caused by environmental or genetic insults.