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Linking Cellular and Whole-Organ Models of Cardiac Metabolism to Predict the Response to Ischemia

Linking Cellular and Whole-Organ Models of Cardiac Metabolism to Predict the Response to Ischemia. Daniel A. Beard, Medical College of Wisconsin Nicolas P. Smith, University of Oxford Edmund J. Crampin, University of Auckland. Mitochondrial Energy Metabolism.

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Linking Cellular and Whole-Organ Models of Cardiac Metabolism to Predict the Response to Ischemia

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  1. Linking Cellular and Whole-Organ Models of Cardiac Metabolism to Predict the Response to Ischemia Daniel A. Beard, Medical College of Wisconsin Nicolas P. Smith, University of Oxford Edmund J. Crampin, University of Auckland

  2. Mitochondrial Energy Metabolism Questions: How is this system physiologically controlled? What happens in disease?

  3. Katz et al. Am J Physiol. (1989) 256:H265-H274. (CARDIAC): Jeneson et al. JBC (1996) 271:27995-27998 (SKELETAL): Control Complex I deficient ANT deficient

  4. Hypotheses for molecular mechanism of Complex-I defficiency • Complex-I proton stoichiometry is 4 • Complex-I proton stoichiometry is 3 • Complex-I proton stoichiometry is 2 • Complex-I proton stoichiometry is 1 • Complex-I proton stoichiometry is 0 Allows us to characterize the molecular mechanism of the disease based on macroscopic clinical data!

  5. Predicted Myocardial Phosphate Levels during Ischemia Simulation Experiment: At constant workload, reduce flow and observe metabolic response.

  6. 3. Oxidative Phosphorylation and Mitochondrial Electophysiology and TCA Cycle and Oxygen Transport

  7. Data are from Zhang et al. Am J Physiol. (2001) 280:H318-H326. [in vivo Dog]

  8. How do we build a model of a complex system?

  9. E + SUC2-⇌ E•SUC2- E•SUC2- + COQ ⇌E•FUM2- + QH2 E•FUM2-⇌E + FUM2- k+1 Enzyme: Succinate Dehydrogenase k-1 k+2 k-2 k+3 k-3 Flux: [A] = [SUC], [B] = [COQ], [P] = [QH2], and [Q] = [FUM]

  10. Parameter Values for Succinate Dehydrogenase Need to document and reconcile all of this information!

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