Sex, stress and UCP2: mitochondria illuminate microglial identity beyond the dichotomy

Abstract

AbstractEnvironmental cues influence microglial interaction with their neuronal landscape, often causing changes in microglial functional identity. This process demands rapid energy production, which is supported by an optimized mitochondrial network. Whether mitochondrial adaptations define a microglial functional state is unknown due to limitations in mitochondrial visualization and manipulation within their microenvironment.Here, we investigate the mitochondrial network of individual microglia in physiological and dysfunctional conditions during a naïve or injury-induced mouse retinal environment. After optic nerve crush (ONC) injury, we identify mitochondrial and microglial phenotypic remodeling that is distinct from the naïve environment. Remarkably, knockout of uncoupling protein 2 (UCP2) causes transient, stress-induced mitochondrial hyperfusion only in males after ONC, even though both sexes suffer from increased intrinsic stress levels. When we compare key metabolic genes between sexes in physiological conditions, only males exhibit a metabolic transition towards glycolysis in the injury-induced environment, which attenuates in UCP2 knockout resulting in acutely accelerated retinal ganglion cell death. Our data shows that the cell-extrinsic ONC environment and cell-intrinsic UCP2KO manipulation triggers several microglial states distinguishable by mitochondrial networks that are heavily influenced by sex and injury-induced stress.