MITOsym®: A Mechanistic, Mathematical Model of Hepatocellular Respiration and Bioenergetics

Area of Science:

• * Computational toxicology
• * Liver bioenergetics modeling
• * In silico drug safety assessment

Background:

• * Drug-induced liver injury (DILI) poses a significant challenge in drug development.
• * Accurate prediction of DILI risk is crucial for patient safety and efficient drug evaluation.
• * Existing models require enhancement to better translate in vitro data to in vivo outcomes.

Purpose of the Study:

• * Introduce MITOsym, a novel mathematical model for hepatocellular respiration and bioenergetics.
• * Integrate MITOsym with the DILIsym® model to predict DILI risk from in vitro screening data.
• * Improve the efficiency of compound evaluation and enhance patient care in drug development.

Main Methods:

• * Incorporate key biochemical pathways: oxidative phosphorylation, electron transport chain, mitochondrial membrane potential, and glycolysis.
• * Utilize published data and new experiments in HepG2 cells to quantify pathway dynamics.
• * Measure oxygen consumption, extracellular acidification, and mitochondrial proton gradient under varying conditions and toxin exposure.

Main Results:

• * MITOsym accurately simulates dynamic changes in hepatocellular oxygen consumption and extracellular acidification rates.
• * The model recapitulates alterations in mitochondrial proton gradient and ATP concentrations.
• * Simulated responses align with known effects of mitochondrial toxins like rotenone, FCCP, and oligomycin.

Conclusions:

• * MITOsym effectively simulates hepatocellular respiration and bioenergetics.
• * The model provides mechanistic insights for translating in vitro data to in vivo hepatotoxicity predictions.
• * MITOsym facilitates the assessment of novel compounds' in vivo human hepatotoxicity risk.