MICROGLIAL ELECTRON TRANSPORT CHAIN SUSTAINS BRAIN DEVELOPMENT WITH DIFFERENT ROLES FOR EACH COMPLEX

Microglia have relevant functions during development, adult maintenance, and brain diseases and is highly dependent on metabolic adaptations. We and others have shown that microglial activity is correlated with upregulation of OXPHOS, suggesting their requirement for normal microglial activation during the critical developmental period or neurological disorders. To investigate the role of OXPHOS in microglial function during development, we generated mouse models deficient for either Complex I or Complex III activity in microglia (MGcCI or MGcCIII) from the embryonic stage. Previously (Mora-Romero et al., 2024), we characterized the MGcCI mouse model and demonstrated that the lack of CI in microglia strongly reduces ATP levels and increases NADH, suggesting reductive stress. Remarkably, MGcCI microglia is highly active at the transcriptional level, passing from a functional state at juvenile age to a dysfunctional state at adult age. Moreover, MGcCI mice develop behavioral deficits and early lethality at 3-months old. To better understand the mechanisms underlying these phenotypes, we generated the MGcCIII mouse model. As expected, MGcCIII microglia show a stronger ATP reduction than MGcCI microglia but a milder decrease of the NADH levels. However, MGcCIII microglia do not show signs of dysfunctionality until 10-months of age, when animals start to develop behavioural problems and start to die. Therefore, we propose that there might be additional mechanisms beyond the lack of ATP that explain the stronger/earlier phenotype observed in MGcCI animals compared to MGcCIII model. To decipher these mechanisms, we are currently conducting a battery of experiments including metabolomics and epigenomics assays.