Abstract
Preterm infants requiring prolonged oxygen therapy often develop cognitive dysfunction in later life. Previously, we reported that 14-week-old young adult mice exposed to hyperoxia as newborns had spatial and learning 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 room 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 while complex I function was decreased at P14 but increased in young adult mice. Proteomic analysis revealed that 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 hippocampal mitochondrial changes may account for cognitive deficits seen in children and adolescents born preterm and may potentially be a contributing mechanism in other oxidative stress associated brain disorders.
Highlights
The long-term detrimental effects of early hyperoxia exposure on lung development and function have been studied in depth, little is known about long-term effect of early hyperoxia exposure on brain development and function
We discovered that hyperoxia exposure during a critical developmental period permanently impairs hippocampal mitochondrial function, alters the expression of specific respiratory chain subunits for complexes I and III, and impairs complex I activity in the hippocampus
As spatial memory deficits and other cognitive problems in the mouse model of bronchopulmonary dysplasia (BPD) correspond to the cognitive deficits seen in adolescents with BPD, these new observations suggest that permanent hippocampal mitochondrial dysfunction induced by early life oxygen exposure as a contributor to the pathophysiology of BPD associated cognitive dysfunction
Summary
The long-term detrimental effects of early hyperoxia exposure on lung development and function have been studied in depth, little is known about long-term effect of early hyperoxia exposure on brain development and function. We have shown that in C57BL/6J mice, hyperoxia (85% oxygen [O2]) exposure during the neonatal period (P2–14) (neonatal hyperoxia) leads to spatial memory and learning deficits, increased exploratory behavior, and shrinkage of area CA1 of the hippocampus when assessed at young adult age (14 weeks)[9]. Www.nature.com/scientificreports to hyperoxia from P2–14 indicated impairments in hippocampal protein synthesis and translation and predicted mitochondrial dysfunction[10]. While mitochondrial dysfunction is associated with the pathogenesis of several neurodegenerative diseases in adults[20], the impact of early-life mitochondrial dysfunction on long-term brain development and function is yet to be determined. Our objective was to determine the long-term changes in hippocampal mitochondrial respiratory complex protein expression and bioenergetic function in neonatal mice (P14) and young adult mice (14 weeks) exposed to hyperoxia from P2–P14
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