Abstract

Preterm infants requiring prolonged oxygen therapy often develop cognitive dysfunction later life. Previously, we reported that 14-week-old young adult mice exposed to hyperoxia as newborns had spatial memory deficits and hippocampal shrinkage. We hypothesized that the underlying mechanism was the induction of hippocampal mitochondrial dysfunction by neonatal hyperoxia. C57BL/6j mouse pups were exposed to 85% oxygen or air from P2 - P14. Hippocampal proteomic analysis was performed in young adult mice (14 weeks). Mitochondrial bioenergetics were measured in neonatal (P14) and young adult mice. We found that hyperoxia exposure reduced mitochondrial ATP-linked oxygen consumption and increased state 4 respiration linked proton leak in both neonatal and young adult mice. Following hyperoxia exposure, complex I function was decreased at P14 but increased in young adult mice. Proteomic analysis revealed that neonatal hyperoxia exposure decreased complex I NDUFB8 and NDUFB11 and complex IV 7B subunits, but increased complex III subunit 9 in young adult mice. In conclusion, neonatal hyperoxia permanently impairs hippocampal mitochondrial function and alters complex I function. These changes may account for memory deficits seen in preterm survivors following prolonged oxygen supplementation and may potentially be a contributing mechanism in other oxidative stress associated cognitive disorders.