Fragmented mitochondria released from microglia trigger A1 astrocytic response and propagate inflammatory neurodegeneration

Abstract

In neurodegenerative diseases, debris of dead neurons are thought to trigger glia-mediated neuroinflammation, thus increasing neuronal death. Here, we show that expression of neurotoxic proteins associated with these diseases in microglia alone is sufficient to trigger death of naïve neurons directly and to propagate neuronal death through activation of naïve astrocytes to A1 state. Injury propagation is mediated, in great part, by the release of fragmented and dysfunctional microglial mitochondria to the neuronal milieu. The amount of damaged mitochondria released from microglia relative to functional mitochondria and the consequent neuronal injury are determined by Fis1-mediated mitochondrial fragmentation within the glia cells. The propagation of inflammatory response and neuronal cell death by extracellular dysfunctional mitochondria suggests a potential new intervention for neurodegeneration – one that inhibits mitochondrial fragmentation in microglia, thus inhibiting the release of dysfunctional mitochondria into the extracellular milieu of the brain, without affecting the release of healthy neuroprotective mitochondria.