Prolonged hyperoxia is a therapeutic backbone for acute respiratory distress syndrome (ARDS), but it itself exacerbates lung injury via mitochondrial dysfunction. Rat models preconditioned to be hyperoxia-tolerant (H-T) or hyperoxia-susceptible (H-S) provide a platform to investigate the mitochondrial basis of differential susceptibility. Integrated computational modeling provides a quantitative and mechanistic framework for understanding lung mitochondrial bioenergetics in rat models with different susceptibility to hyperoxia-induced ARDS. We developed a thermodynamically constrained computational model of lung mitochondrial bioenergetics, which incorporates critical regulatory mechanisms of mitochondrial enzymatic reactions and transporters by ions (Ca 2+ , H + ) and metabolites, absent in previous models. The model was separately parameterized using experimental respirometry data from mitochondria isolated from lungs of H-T, H-S, and normoxia rats in the presence of multiple substrates (pyruvate+malate, glutamate+malate, and succinate ± rotenone) and ADP concentrations. Model parameterization revealed distinct bioenergetic profiles between groups. H-S mitochondria showed reduced activity in several key components, including adenine nucleotide translocase (ANT), cytochrome c oxidase (CIV), complex I (CI), and glutamate-oxaloacetate transaminase (GOT). In contrast, H-T mitochondria demonstrated an adaptive profile characterized by increased activity of ANT, CIV, and proton leak (Hleak). When subjected to computational simulations of ARDS, including increased proton leak, calcium overload, and complex I inhibition, the model predicted divergent outcomes. H-S mitochondrial dysfunction was characterized by redox collapse, loss of membrane potential, and ATP depletion. Meanwhile, H-T mitochondria maintained bioenergetic homeostasis through enhanced electron supply via CI and CII, coupled with higher activity of CIV. This metabolic flexibility allowed H-T mitochondria to compensate for impaired complex I activity under stress. The new computational model with ion and metabolic regulators provides a platform for identifying critical mitochondrial processes and therapeutic strategies to mitigate mitochondrial dysfunction in ARDS.
Taheri et al. (Sun,) studied this question.