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We developed a comprehensive computational model of lung mitochondrial bioenergetics that integrates key regulatory mechanisms. The model, parameterized using respirometry data from lung mitochondria of hyperoxia-tolerant and -susceptible rats, identified adenine nucleotide translocase, cytochrome c oxidase, and proton leak as critical determinants of lung mitochondrial bioenergetic homeostasis. Model simulations predict that deficits in these processes drive rapid bioenergetic failure in the lungs of hyperoxia-susceptible rats. 

Mitochondrial Ca²⁺uptake is mediated by the mitochondrial calcium uniporter complex (MCUx), in which MICU1/2 serve as cytosolic Ca2+-sensing gatekeepers that set a Ca²⁺-dependent activation threshold. Coordinated control of MCUx activity is critical because mitochondrial Ca²⁺uptake couples cytosolic Ca²⁺signals to metabolic activation and must be regulated to prevent mitochondrial Ca²⁺overload and bioenergetic dysfunction. We developed a mechanistic model that incorporates explicit MICU1/2-dependent MCUx gatekeeping and a thermodynamically constrained Ca²⁺transport formulation that accounts for Mg²⁺inhibition and membrane potential dependence. Cytosolic and mitochondrial Ca²⁺dynamics were simulated by integrating the MCUx model into a mitochondrial cation-handling model under multiple Ca²⁺stimulation protocols. Because matrix-side Ca²⁺regulation of MCUx remains controversial, we also evaluated a putative matrix-side regulatory mechanism by comparing simulations with and without an added matrix-side regulatory module, rather than assuming such regulation as a required feature of the MCUx model. The model reproduces key experimental behaviors across genotypes. In wild-type mitochondria, MCUx-mediated Ca²⁺ uptake is negligible below a cytosolic Ca²⁺threshold (~0.2 µM), whereas MICU1-knockout mitochondria show constitutive uptake and MICU2-knockout mitochondria exhibit an intermediate, lowered threshold. Inclusion of matrix-side MCUx regulation transiently attenuated MCUx-mediated Ca²⁺ uptake over an intermediate mitochondrial Ca²⁺range, producing higher transient cytosolic Ca²⁺and lower transient mitochondrial Ca²⁺, while both cases approached similar steady states. In addition, cytosolic Mg²⁺acts as a graded inhibitor of MCUx-mediated Ca²⁺uptake, limiting mitochondrial Ca²⁺loading. These results provide a quantitative framework for coupled cytosolic-mitochondrial Ca²⁺ dynamics across diverse conditions. 

We investigated sex-specific responses to hyperoxia-induced acute lung injury (HALI) in rats. Female rats exhibited attenuated severity, with less pleural effusion, pulmonary edema, and apoptosis than males. Studies in isolated mitochondria, lung tissue homogenates, and isolated lungs indicate that this attenuated severity is associated with mitochondrial adaptations and enhanced tissue H₂O₂scavenging capacity. These findings underscore the importance of sex as a biological variable and identify mitochondrial complex II as a potential HALI therapeutic target. 

We examined sex-specific and substrate-dependent differences in liver mitochondrial function of adult SD rats. Liver mitochondria preferentially use GM over PM for respiration, whereas PM produces more H₂O₂. Female mitochondria exhibited higher respiration and H₂O₂production than males across all substrates, likely driven by hormonal factors and sex-specific regulatory pathways. These findings highlight the importance of both substrate and sex in shaping liver mitochondrial bioenergetics and redox function, offering insight into intrinsic metabolic differences. 

ABSTRACT Voltage‐dependent anion channel (VDAC) is the primary conduit for regulated passage of ions and metabolites into and out of a mitochondrion. Calculating the solvation free energy for VDAC is crucial for understanding its stability, function, and interactions within the cellular environment. In this article, numerical schemes for computing the total solvation free energy for VDAC—comprising electrostatic, ideal gas, and excess free energies plus the nonpolar energy—are developed based on a nonuniform size modified Poisson–Boltzmann ion channel (nuSMPBIC) finite element solver along with tetrahedral meshes for VDAC proteins. The current mesh generation package is also updated to improve mesh quality and accelerate mesh generation. A VDAC Solvation Free Energy Calculation (VSFEC) package is then created by integrating these schemes with the updated mesh package, the nuSMPBIC finite element package, the PDB2PQR package, and the OPM database, as well as one uniform SMPBIC finite element package and one Poisson–Boltzmann ion channel (PBIC) finite element package. With the VSFEC package, many numerical experiments are made using six VDAC proteins, eight ionic solutions containing up to four ionic species, including ATP⁴⁻and Ca²⁺, two reference states, different boundary values, and different permittivity constants. The test results underscore the importance of considering nonuniform ionic size effects to explore the varying patterns of the total solvation free energy, and demonstrate the high performance of the VSFEC package for VDAC solvation free energy calculation. 

We developed a computational model of sodium fluorescein (SF) biliary excretion in ex vivo machine perfusion and used this model to assess changes in model parameters associated with the activity of MRP2, a hepatocyte membrane transporter, in response to increasing warm ischemia time. We found a significant decrease in the parameter value describing MRP2 activity, consistent with a role of decreased MRP2 function in ischemia-reperfusion injury leading to decreased secretion of SF into bile. 

We assessed lung tissue mitochondrial bioenergetics in rats with tolerance (H-T) or susceptibility (H-S) to hyperoxia-induced ARDS. Results from studies in isolated mitochondria, tissue homogenate, and isolated perfused lungs show that mitochondrial bioenergetics are differentially altered in H-T and H-S lungs suggesting a potential role for mitochondrial bioenergetics in hyperoxia-induced ARDS. Results are clinically relevant since hyperoxia exposure is a primary therapy for patients with ARDS, and differential sensitivity to hyperoxia surely occurs in humans. 

The suprachiasmatic nucleus (SCN) sets the phase of oscillation throughout the brain and body. Anatomical evidence reveals a portal system linking the SCN and the organum vasculosum of the lamina terminalis (OVLT), begging the question of the direction of blood flow and the nature of diffusible signals that flow in this specialized vasculature. Using a combination of anatomical and in vivo two-photon imaging approaches, we unequivocally show that blood flows unidirectionally from the SCN to the OVLT, that blood flow rate displays daily oscillations with a higher rate at night than in the day, and that circulating vasopressin can access portal vessels. These findings highlight a previously unknown central nervous system communication pathway, which, like that of the pituitary portal system, could allow neurosecretions to reach nearby target sites in OVLT, avoiding dilution in the systemic blood. In both of these brain portal pathways, the target sites relay signals broadly to both the brain and the rest of the body.