Mitochondrial network adaptations of microglia reveal sex-specific stress response after injury and UCP2 knockout
Margaret E Maes1, Gloria Colombo1, Florianne E Schoot Uiterkamp1
1Institute of Science and Technology Austria (ISTA), Am Campus 1, 3400 Klosterneuburg, Austria.
Abstract:
Mitochondrial networks remodel their connectivity, content, and subcellular localization to support optimized energy production in conditions of increased environmental or cellular stress. Microglia rely on mitochondria to respond to these stressors, however our knowledge about mitochondrial networks and their adaptations in microglia in vivo is limited. Here, we generate a mouse model that selectively labels mitochondria in microglia. We identify that mitochondrial networks are more fragmented with increased content and perinuclear localization in vitro vs. in vivo. Mitochondrial networks adapt similarly in microglia closest to the injury site after optic nerve crush. Preventing microglial UCP2 increase after injury by selective knockout induces cellular stress. This results in mitochondrial hyperfusion in male microglia, a phenotype absent in females due to circulating estrogens. Our results establish the foundation for mitochondrial network analysis of microglia in vivo, emphasizing the importance of mitochondrial-based sex effects of microglia in other pathologies.
Insights
Microglia use mitochondria to respond to stress. This study reveals differences in microglial mitochondrial networks in vitro versus in vivo, and identifies sex-based differences in response to injury.
Area of Science:
- Neuroscience
- Cell Biology
- Immunology
Background:
- Microglia are crucial immune cells in the central nervous system.
- Mitochondria are vital for cellular energy production and stress response.
- Understanding microglial mitochondrial dynamics in vivo is limited.
Purpose of the Study:
- To investigate mitochondrial network adaptations in microglia in vivo.
- To compare microglial mitochondrial morphology in vitro and in vivo.
- To explore the role of UCP2 in microglial response to injury and sex-based differences.
Main Methods:
- Generated a novel mouse model for selective mitochondrial labeling in microglia.
- Utilized in vitro and in vivo imaging techniques.
- Performed optic nerve crush injury model and selective UCP2 knockout.
Main Results:
- Microglial mitochondrial networks are more fragmented and perinuclear in vitro compared to in vivo.
- Mitochondrial networks adapt similarly in microglia near injury sites.
- Loss of UCP2 leads to cellular stress and mitochondrial hyperfusion in male microglia, but not females.
Conclusions:
- Established a foundation for analyzing microglial mitochondrial networks in vivo.
- Highlighted significant differences in mitochondrial morphology between in vitro and in vivo microglia.
- Demonstrated sex-specific mitochondrial adaptations in microglia, influenced by estrogens, impacting injury response.
