MITOsym®: A mechanistic, mathematical model of hepatocellular respiration and bioenergetics

Pharmaceutical Research

Volumn 32, Issue 6, 2015, Pages 1975-1992

  Yang, Y ^a   Nadanaciva, S ^b   Will, Y ^b   Woodhead, J L ^a   Howell, B A ^a   Watkins, P B ^a   Siler, S Q ^a  

^a HAMNER INSTITUTES FOR HEALTH SCIENCES   (United States)

^b PFIZER INC   (United States)

Author keywords

Bioenergetics; Extracellular acidification rate; Mechanism based; Mitochondrial toxicity; Oxygen consumption rate

Indexed keywords

ADENOSINE TRIPHOSPHATE; CARBONYL CYANIDE 4 (TRIFLUOROMETHOXY)PHENYLHYDRAZONE; GLUCOSE; OLIGOMYCIN; OXYGEN; PROTON; ROTENONE; UNCOUPLING PROTEIN;

ACIDIFICATION; ARTICLE; BIOENERGY; CELL RESPIRATION; COMPUTER SIMULATION; CONTROLLED STUDY; DRUG BLOOD LEVEL; DRUG DESIGN; DRUG EFFECT; DYNAMICS; FEEDBACK SYSTEM; GLYCOLYSIS; HEPG2 CELL LINE; HUMAN; HUMAN CELL; IN VITRO STUDY; LIVER CELL; LIVER TOXICITY; MATHEMATICAL MODEL; MITOCHONDRIAL MEMBRANE POTENTIAL; MITOCHONDRIAL RESPIRATION; MITOCHONDRION; MITOSYM; OXIDATIVE PHOSPHORYLATION; OXYGEN CONSUMPTION; PATIENT CARE; PRIORITY JOURNAL; RESPIRATORY CHAIN; BIOLOGICAL MODEL; CHEMICAL AND DRUG INDUCED LIVER INJURY; DOSE RESPONSE; DRUG EFFECTS; ENERGY METABOLISM; HEP-G2 CELL LINE; LIVER; LIVER MITOCHONDRION; METABOLISM; PATHOLOGY; PH; RISK ASSESSMENT; TIME FACTOR;

ADENOSINE TRIPHOSPHATE; CARBONYL CYANIDE P-TRIFLUOROMETHOXYPHENYLHYDRAZONE; CELL RESPIRATION; CHEMICAL AND DRUG INDUCED LIVER INJURY; COMPUTER SIMULATION; DOSE-RESPONSE RELATIONSHIP, DRUG; ENERGY METABOLISM; HEP G2 CELLS; HEPATOCYTES; HUMANS; HYDROGEN-ION CONCENTRATION; LIVER; MEMBRANE POTENTIAL, MITOCHONDRIAL; MITOCHONDRIA, LIVER; MODELS, BIOLOGICAL; OXYGEN CONSUMPTION; RISK ASSESSMENT; ROTENONE; TIME FACTORS; UNCOUPLING AGENTS;

EID: 84934989784     PISSN: 07248741     EISSN: 1573904X     Source Type: Journal    
DOI: 10.1007/s11095-014-1591-0     Document Type: Article

References (40)

1. Suk KT, KimDJ.Drug-induced liver injury: present and future. Clin Mol Hepatol. 2012;18(3):249-57.
2. Marroquin LD, Hynes J, Dykens JA, Jamieson JD, Will Y. Circumventing the Crabtree effect: replacing media glucose with galactose increases susceptibility of HepG2 cells to mitochondrial toxicants. Toxicol Sci Off J Soc Toxicol. 2007;97(2):539-47.
3. Nadanaciva S, Rana P, Beeson GC, Chen D, Ferrick DA, Beeson CC, et al. Assessment of drug-induced mitochondrial dysfunction via altered cellular respiration and acidification measured in a 96-well platform. J Bioenerg Biomembr. 2012;44(4):421-37.
4. Brand MD, Nicholls DG. Assessing mitochondrial dysfunction in cells. Biochem J. 2011;435(2):297-312.
5. Hynes J,Marroquin LD,OgurtsovVI, ChristiansenKN, StevensGJ, Papkovsky DB, et al. Investigation of drug-induced mitochondrial toxicity using fluorescence-based oxygen-sensitive probes. Toxicol Sci Off J Soc Toxicol. 2006;92(1):186-200.
6. Ferrick DA, Neilson A, Beeson C. Advances in measuring cellular bioenergetics using extracellular flux. Drug Discov Today. 2008;13(5-6):268-74.
7. WuM,Neilson A, Swift AL,Moran R, Tamagnine J, ParslowD, et al. Multiparameter metabolic analysis reveals a close link between attenuated mitochondrial bioenergetic function and enhanced glycolysis dependency in human tumor cells. Am J Physiol Cell Physiol. 2007;292(1):C125-36.
8. Howell BA, Yang Y, Kumar R, Woodhead JL, Harrill AH, Clewell 3rd HJ, et al. In vitro to in vivo extrapolation and species response comparisons for drug-induced liver injury (DILI) using DILIsymTM: a mechanistic, mathematical model of DILI. J Pharmacokinet Pharmacodyn. 2012;39(5):527-41.
9. Felser A, Blum K, Lindinger PW, Bouitbir J, Krähenbühl S. Mechanisms of hepatocellular toxicity associated with dronedarone-a comparison to amiodarone. Toxicol Sci Off J Soc Toxicol. 2013;131(2):480-90.
10. Zahno A, Brecht K, Morand R, Maseneni S, Török M, Lindinger PW, et al. The role of CYP3A4 in amiodarone-associated toxicity on HepG2 cells. Biochem Pharmacol. 2011;81(3):432-41.
11. Mullen PJ, Zahno A, Lindinger P,Maseneni S, Felser A,Krähenbühl S, et al. Susceptibility to simvastatin-induced toxicity is partly determined bymitochondrial respiration and phosphorylation state of Akt. Biochim Biophys Acta. 2011;1813(12):2079-87.
12. NissimI, Horyn O, Nissim I, Daikhin Y,Wehrli SL, YudkoffM, et al. Effects of a glucokinase activator on hepatic intermediary metabolism: study with 13C-isotopomer-based metabolomics. Biochem J. 2012;444(3):537-51.
13. Hafner RP, Brown GC, Brand MD. Analysis of the control of respiration rate, phosphorylation rate, proton leak rate and protonmotive force in isolated mitochondria using the "top-down" approach of metabolic control theory. Eur J Biochem FEBS. 1990;188(2):313-9.
14. Ainscow EK, Brand MD. Top-down control analysis of ATP turnover, glycolysis and oxidative phosphorylation in rat hepatocytes. Eur J Biochem FEBS. 1999;263(3):671-85.
15. Zoratti M, Petronilli V. Multiple relationships between rate of oxidative phosphorylation and delta microH in rat liver mitochondria. FEBS Lett. 1985;193(2):276-82.
16. Dykens JA, Jamieson JD, Marroquin LD, Nadanaciva S, Xu JJ, Dunn MC, et al. In vitro assessment of mitochondrial dysfunction and cytotoxicity of nefazodone, trazodone, and buspirone. Toxicol Sci Off J Soc Toxicol. 2008;103(2):335-45.
17. Berg JM, Tymoczko JL, Stryer L. The glycolytic pathway is tightly controlled [Internet]. 2002 [cited 2013 Sep 19]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK22395/.
18. Maier K, Hofmann U, Reuss M, Mauch K, Niebel A, Vacun G. Identification of metabolic fluxes in hepatic cells from transient 13Clabeling experiments: Part I. Experimental observations. Biotechnol Bioeng. 2008;100(2):355-70.
19. Okamoto T, Kanemoto N, Ban T, Sudo T, Nagano K, Niki I. Establishment and characterization of a novel method for evaluating gluconeogenesis using hepatic cell lines, H4IIE and HepG2. Arch Biochem Biophys. 2009;491(1-2):46-52.
20. http://www.seahorsebio.com/learning/app-notes/atp-vsbioenergetic.php. Understanding the Relationship Between Bioenergetic Rates and ATP Turnover [Internet]. Seahorse Bioscience; 2013. Available from: http://www.seahorsebio.com/learning/app-notes/atp-vs-bioenergetic.php.
21. Brown RP, Delp MD, Lindstedt SL, Rhomberg LR, Beliles RP. Physiological parameter values for physiologically based pharmacokinetic models. Toxicol Ind Health. 1997;13(4):407-84.
22. Perry SW, Norman JP, Barbieri J, Brown EB, Gelbard HA. Mitochondrial membrane potential probes and the proton gradient: a practical usage guide. BioTechniques. 2011;50(2):98-115.
23. Palmeira CM, Moreno AJ, Madeira VM, Wallace KB. Continuous monitoring of mitochondrial membrane potential in hepatocyte cell suspensions. J Pharmacol Toxicol Methods. 1996;35(1):35-43.
24. Berthiaume F, MacDonald AD, Kang YH, Yarmush ML. Control analysis of mitochondrial metabolism in intact hepatocytes: effect of interleukin-1β and interleukin-6. Metab Eng. 2003;5(2):108-23.
25. Leverve XM, Fontaine E, Putod-Paramelle F, Rigoulet M. Decrease in cytosolic ATP/ADP ratio and activation of pyruvate kinase after in vitro addition of almitrine in hepatocytes isolated from fasted rats. Eur J Biochem FEBS. 1994;224(3):967-74.
26. Abe Y, Sakairi T, Kajiyama H, Shrivastav S, Beeson C, Kopp JB. Bioenergetic characterization of mouse podocytes. Am J Physiol Cell Physiol. 2010;299(2):C464-76.
27. Shoda LKM, Woodhead JL, Siler SQ, Watkins PB, Howell BA. Linking physiology to toxicity usingDILIsym(®), amechanisticmathematical model of drug-induced liver injury. BiopharmDrug Dispos. 2014;35(1):33-49.
28. Seitz HJ,MüllerMJ, KroneW, Tarnowski W. Coordinate control of intermediary metabolism in rat liver by the insulin/glucagon ratio during starvation and after glucose refeeding. Regulatory significance of long-chain acyl-CoA and cyclic AMP. Arch Biochem Biophys. 1977;183(2):647-63.
29. Rossignol R, Gilkerson R, Aggeler R, Yamagata K, Remington SJ, Capaldi RA. Energy substrate modulates mitochondrial structure and oxidative capacity in cancer cells. Cancer Res. 2004;64(3):985-93.
30. Hue L, Sobrino F, Bosca L. Difference in glucose sensitivity of liver glycolysis and glycogen synthesis. Relationship between lactate production and fructose 2,6-bisphosphate concentration. Biochem J. 1984;224(3):779-86.
31. Johnson-Cadwell LI, Jekabsons MB, Wang A, Polster BM, Nicholls DG. "MildUncoupling" does not decreasemitochondrial superoxide levels in cultured cerebellar granule neurons but decreases spare respiratory capacity and increases toxicity to glutamate and oxidative stress. J Neurochem. 2007;101(6):1619-31.
32. Hatafi Y. The structural basis of membrane function. Academic Press; 2012. 501 p.
33. Schmitz JPJ, Groenendaal W, Wessels B, Wiseman RW, Hilbers PAJ, Nicolay K, et al. Combined in vivo and in silico investigations of activation of glycolysis in contracting skeletal muscle. Am J Physiol Cell Physiol. 2013;304(2):C180-93.
34. Nieminen AL, Saylor AK, Herman B, Lemasters JJ. ATP depletion rather than mitochondrial depolarization mediates hepatocyte killing after metabolic inhibition. Am J Physiol. 1994;267(1 Pt 1):C67-74.
35. Weinberg F, Hamanaka R, Wheaton WW, Weinberg S, Joseph J, Lopez M, et al. Mitochondrial metabolism and ROS generation are essential for Kras-mediated tumorigenicity. Proc Natl Acad Sci. 2010;107(19):8788-93.
36. Gohil VM, Sheth SA, Nilsson R, Wojtovich AP, Lee JH, Perocchi F, et al. Nutrient-sensitized screening for drugs that shift energy metabolism from mitochondrial respiration to glycolysis. Nat Biotechnol. 2010;28(3):249-55.
37. Beard DA. A Biophysical model of the mitochondrial respiratory systemand oxidative phosphorylation. PLoS Comput Biol [Internet]. 2005 [cited 2013 May 5];1(4). Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1201326/.
38. Cortassa S, Aon MA, Marbán E, Winslow RL, O'Rourke B. An integrated model of cardiac mitochondrial energy metabolism and calcium dynamics. Biophys J. 2003;84(4):2734-55.
39. Wei A-C, Aon MA, O'Rourke B, Winslow RL, Cortassa S. Mitochondrial energetics, pH regulation, and ion dynamics: a computational-experimental approach. Biophys J. 2011;100(12): 2894-903.
40. Dash RK, DiBella JA, Cabrera ME. A computational model of skeletal muscle metabolism linking cellular adaptations induced by altered loading states to metabolic responses during exercise. Biomed Eng OnLine. 2007;6:14.