Neuron-Specific Mitochondrial Oxidative Stress Results in Glucose Dysregulation and a Striking Astrocyte Response

Abstract

Mitochondrial superoxide (O2.-) production is implicated in aging, neurodegenerative disease, and most recently epilepsy. Yet the specific contribution of neuronal O2.- to these phenomenon is unclear. Here, we selectively deleted superoxide dismutase-2 (SOD2) in neuronal basic helix-loop-helix transcription factor (NEX)-expressing cells restricting deletion to a subset of excitatory principle neurons primarily in the forebrain (cortex and hippocampus). This resulted in nSOD2 KO mice that lived into adulthood (2-3 months) with epilepsy, selective loss of neurons, metabolic rewiring and a marked mitohormetic gene response. Surprisingly, expression of an astrocytic gene, glial fibrillary acidic protein (GFAP) was significantly increased relative to WT. Further studies in rat primary neuron-glial cultures showed that increased mitochondrial O2.- was sufficient to upregulate GFAP suggesting that mitochondrial O2.- originating in neurons is sufficient to upregulate astrocytic GFAP. These results suggest that neuron-specific mitochondrial O2.- is sufficient to drive a complex and catastrophic epileptic phenotype and highlights the ability of SOD2 to act in a cell-nonautonomous manner to influence an astrocytic response.