title: MITOsym®: A Mechanistic, Mathematical Model of Hepatocellular Respiration and Bioenergetics.
abstract: OBJECTIVE
  MITOsym, a new mathematical model of hepatocellular respiration and bioenergetics, has been developed in partnership with the DILIsym® model with the purpose of translating in vitro compound screening data into predictions of drug induced liver injury (DILI) risk for patients. The combined efforts of these two models should increase the efficiency of evaluating compounds in drug development in addition to enhancing patient care.
  
  
  METHODS
  MITOsym includes the basic, essential biochemical pathways associated with hepatocellular respiration and bioenergetics, including mitochondrial oxidative phosphorylation, electron transport chain activity, mitochondrial membrane potential, and glycolysis; also included are dynamic feedback signals based on perturbation of these pathways. The quantitative relationships included in MITOsym are based primarily on published data; additional new experiments were also performed in HepG2 cells to determine the effects on oxygen consumption rate as media glucose concentrations or oligomycin concentrations were varied. The effects of varying concentrations of FCCP on the mitochondrial proton gradient were also measured in HepG2 cells.
  
  
  RESULTS
  MITOsym simulates and recapitulates the reported dynamic changes to hepatocellular oxygen consumption rates, extracellular acidification rates, the mitochondrial proton gradient, and ATP concentrations in the presence of classic mitochondrial toxins such as rotenone, FCCP, and oligomycin.
  
  
  CONCLUSIONS
  MITOsym can be used to simulate hepatocellular respiration and bioenergetics and provide mechanistic hypotheses to facilitate the translation of in vitro data collection to predictions of in vivo human hepatotoxicity risk for novel compounds.
authors.affiliation: Institute for Drug Safety Sciences, The Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Yang
authors.forename: S
authors.initials: S
authors.lastname: Nadanaciva
authors.forename: Y
authors.initials: Y
authors.lastname: Will
authors.forename: J L
authors.initials: JL
authors.lastname: Woodhead
authors.forename: B A
authors.initials: BA
authors.lastname: Howell
authors.forename: P B
authors.initials: PB
authors.lastname: Watkins
authors.forename: S Q
authors.initials: SQ
authors.lastname: Siler
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone / Q000633:toxicity; D019069:Cell Respiration / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D004734:Energy Metabolism / Q000187:drug effects*; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008954:Models, Biological; D010101:Oxygen Consumption / Q000187:drug effects; D018570:Risk Assessment; D012402:Rotenone / Q000633:toxicity; D013997:Time Factors; D014475:Uncoupling Agents / Q000633:toxicity
chemical_list: D014475:Uncoupling Agents; D012402:Rotenone; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone; D000255:Adenosine Triphosphate