Early Life Supraphysiological Levels of Oxygen Exposure Permanently Impairs Hippocampal Mitochondrial Function

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.

Regulation of hyperoxia-induced neonatal lung injury via post-translational cysteine redox modifications

“…Downregulated expression of these proteins could lead to mitochondrial dysfunction, especially NDUS1, NU2M, or NDUV2, which are core subunits for function and structure of complex I in the mitochondria [ 51 , 52 ]. A similar finding on reduced expression of complex I mitochondrial proteins following 85% oxygen was previously reported [ 53 ] and hyperoxia-induced mitochondrial damage is also proposed to cause simplification of lung structure, or bronchopulmonary dysplasia (BPD) in infant lungs [ 54 ].

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Prolonged oxygen exposure causes the mobilization and functional damage of stem or progenitor cells and exacerbates cardiac ischemia or reperfusion injury in healthy mice

“…Several past studies have shown the beneficial effects of oxygen administration to patients with critical disorders (Bourke et al, 2018; Golledge & Singh, 2019; Jaber et al, 2016; Levy et al, 2016; Martin & Grocott, 2013; Moradkhan & Sinoway, 2010; Renda et al, 2018; Rockswold et al, 2013; Weaver et al, 2002) as well as to healthy individuals, such as athletes (Ishii et al, 2005; Kujawski et al, 2020). Conversely, the issue of oxygen toxicity is also well known, as molecular oxygen induces cell damage directly or indirectly by interacting with other free radicals (Ciarlone et al, 2019; Frank et al, 1978; Kuksal et al, 2017; Matute‐Bello et al, 2008; Ramani et al, 2019). Although the precise mechanism is yet to be completely understood, oxygen toxicity can largely vary depending on the types of cells/organs, the systemic/regional pathophysiological conditions, and the oxygen administration parameters (such as time, concentration, and pressure; Fandler‐Höfler et al, 2020; Frank et al, 1978; Matute‐Bello et al, 2008).…”

“…Excessive oxygen exposure may induce severe damage to normal tissue (stem) cells; however, there remains an absence of consensus regarding the optimal oxygen concentration and administration duration under particular pathophysiological conditions. The harmful effects of oxygen intake at increased partial pressures are most often reflected in the central nervous system and lungs (Chu et al, 2018; Ciarlone et al, 2019; Davis et al, 1983; Ramani et al, 2019; Taccone et al, 2018). Therefore, the risk‐benefit balance based on individual pathophysiological conditions should be evaluated carefully, following which an optimal oxygen administration schedule should be designed to provide the optimum benefits (Brugniaux et al, 2018; Chu et al, 2018; Fandler‐Höfler et al, 2020; Lumb & Walton, 2012; Rocco et al, 2014; Taccone et al, 2018).…”

“…Oxygen is also occasionally administered to healthy individuals, such as athletes, for enhancing performance during sports events, such as races (Ishii et al, 2005; Kujawski et al, 2020). Although oxygen is essential for life, prolonged exposure to oxygen at high concentrations may induce cellular toxicity, especially in the lungs and central nervous system (Chu et al, 2018; Davis et al, 1983; Ramani et al, 2019; Taccone et al, 2018). Side effects are observed in certain cases, especially in patients undergoing hyperbaric oxygenation for long durations (Ciarlone et al, 2019).…”