Caffeine, MitoQ, and GABA Prophylaxis of Mitochondrial Dysfunction Induced in Human Pulmonary Cells by Normobaric-Hyperoxia and Hyperbaric-Hyperoxia.

Exposure to hyperoxia lasting either a few days at normobaria or a few hours at hyperbaria induces pulmonary oxygen toxicity. Cellular functional changes resulting from oxygen toxicity include alterations in both mitochondrial dynamics and bioenergetics. The primary goal of this study was to quantify the prophylactic effects of three compounds, caffeine, MitoQ, and γ-aminobutyric acid (GABA), to protect human pulmonary cells in vitro from mitochondrial alterations induced by normobaric- and hyperbaric-hyperoxic conditions. Using cultured lung microvascular and pulmonary artery endothelial cells as well as A549 cells, we examined mitochondrial dynamic and bioenergetics function following exposure to normobaric-hyperoxic (5% CO₂ and 95% O₂ for 72 h) and hyperbaric-hyperoxic (~5% CO₂ equivalent and remainder O₂ at pressure of 4.8 atmosphere absolute (ATA) for 4 h) conditions in the presence of the drugs. Mitochondrial respiration parameters, inner membrane potential, motility, intracellular distribution, and size were measured, along with quantitation of respiration complex levels. Redistribution of intracellular ATP-linked respiration was determined. Comparisons of results were made to controls under normobaric-normoxic conditions. Effects of the drugs under control conditions were also measured. Presence of the drugs resulted in differential effects on hyperoxia-induced alterations in cellular respiration function, stability of mitochondrial potential, and distribution of ATP-linked respiration within the cell. Inclusion of these drugs also produced unique signatures for respiration complex protein levels. Moreso for caffeine than for MitoQ and GABA, its inclusion in the face of hyperoxic exposure served to preserve mitochondrial bioenergetics function, primarily by promoting intracellular redistribution of mitochondrial volume to the perinuclear space. These results indicate a potential role for pharmacologic prophylaxis via therapeutics targeted to support mitochondrial function as a means of protecting the lung from hyperoxia-induced pulmonary cellular oxygen toxicity.