Computational Modeling of Substrate-Dependent Lung Mitochondrial Respiration and Bioenergetics in Rats with Different Susceptibility to Hyperoxia-Induced ARDS

Prolonged exposure to high oxygen levels (hyperoxia) is unavoidable in managing severe Acute Respiratory Distress Syndrome (ARDS), but can itself worsen lung injury and increase mortality. Rats conditioned to be hyperoxia-tolerant (H-T) or hyperoxia-susceptible (H-S) provide a system for assessing the contribution of mitochondrial bioenergetics to the differential susceptibility to hyperoxia-induced ARDS and for identifying potential therapeutic targets. Due to the system's complexity, interpreting lung mitochondrial bioenergetics data from these rat models requires a computational model to define which processes are altered and how changes influence overall lung tissue bioenergetics. We developed a thermodynamically constrained computational model of lung mitochondrial bioenergetics that extends prior models by incorporating regulation by ions (Ca 2⁺ , H ⁺ , etc.) and metabolites. The model was parameterized using experimental respirometry data from isolated lung mitochondria of conditioned (H-T, H-S) and control rats with different substrates and ADP concentrations. Model parameterization showed distinct bioenergetic changes. H-S mitochondria had reduced activity in adenine nucleotide translocase (ANT), cytochrome c oxidase (CIV), complex I (CI), and glutamate-oxaloacetate transaminase (GOT). Conversely, H-T mitochondria showed an increased activity of ANT and CIV. This supports greater metabolic flexibility in H-T mitochondria compared to H-S. Simulations of ARDS-related changes predicted divergent outcomes. H-S mitochondria underwent rapid failure, with redox collapse, loss of membrane potential, and ATP depletion. H-T mitochondria maintained bioenergetic homeostasis by enhancing electron supply via CI and complex II, with higher CIV activity. This comprehensive computational model provides a framework for identifying critical mitochondrial processes and therapeutic strategies to mitigate mitochondrial dysfunction in ARDS.