1. Coordination of Intermediary Metabolism

2. ATP Homeostasis Energy Consumption (adult woman/day) –6300-7500 kJ (>200 mol ATP) –Vigorous exercise: 100x rate of ATP utilization Steady-State ATP: <0.1 mol –0.05% daily usage –<1 min supply Strict Coordinate Control

3. Glycogenolysis (glycogen metabolism) Glycolysis Citric Acid Cycle Oxidative Phosphorylation

4. Identification of Potential Control Sites in Electron Transport and Oxidative Phosphorylation

5. Complex I and III 1/2 NADH + Cytochrome c (Fe 3+ ) + ADP + P i —— > 1/2 NAD + + Cytochrome c (Fe 2+ ) + ATP ∆G ’ = ~0 (reversible)

6. Complex I and III Equilibrium ATP Mass Action Ratio (compare with Energy Charge)

7. Cytochrome c Oxidase Complex IV Irreversible Regulatory Site

8. Control by Substrate Availability Inverse ATP Mass Action Ratio [NADH] and [ATP]  reduced Cytc c

9. Effectors of Electron Transport - Oxidative Phosphorylation ATP mass action ratio –Availability of ADP and Pi Stimulation by Ca 2+ IF 1 : inhibitor of F 1 –ATPase

10. IF 1 (Inhibitor of F 1 –ATPase) Inactive during active respiration Traps ATP bound to  DP Prevents ATPase activity when [O 2 ] is low

11. Sources of Electrons for Mitochondrial Electron Transport Glycolysis (or glycogenolysis) Fatty acid degradation Citric Acid Cycle Amino acid degradation

12. Figure 17-1 Metabolic Relationships

13. Figure 17-16 Regulation of the Citric Acid Cycle Inhibition of ETC  NADH

14. Coordinate Regulation of Citric Acid Cycle

15. Coordinate Regulation of Glycolysis and Pyruvate Dehydrogenase Citrate

16. Inhibition of Phosphofructokinase by Citrate

17. Decline in Demand for ATP (ATP  and ADP  ) Isocitrate Dehydrogenase: not activated by ADP α-Ketoglutarate Dehydrogenase: inhibited by ATP Citrate Accumulates –Citrate transport system –Inhibition of Phosphofructokinase

18. Regulation of Central Metabolic Pathways

19. Advantages of Aerobic Metabolism Anaerobic glycolysis: 2 ATP C 6 H 12 O 6 + 2 ADP + 2 P i — > 2 Lactate + 2 H + + 2 H 2 O + 2 ATP Aerobic metabolism of glucose: 32 ATP C 6 H 12 O 6 + 32 ADP + 32 P i + 6 O 2 — > 6 CO 2 + 38 H 2 O + 32 ATP

20. Drawbacks or Disadvantages of Aerobic Metabolism Sensitivity to O 2 Deprivation Production of Reactive Oxygen Species (ROS)

21. Oxygen Deprivation in Heart Attack and Stroke Myocardial Infarction: interuption of the blood (O 2 ) supply to a portion of the heart Stroke: interuption of the blood (O 2 ) supply to a portion of the brain

22. Consequences of O 2 Limitation Disruption of osmotic balance (ion pumps) Swelling of cells and organelles — increased permeability Acidification (anaerobic lactic acid production) — activity of leaked lysosomal enzymes

23. Partial Oxygen Reduction Produces Reactive Oxygen Species (ROS) Superoxide Radical Hydroxyl Radical

24. Radicals Extract Electrons (Oxidize) Various Biomolecules Polyunsaturated Lipids — disrupts biological membranes DNA — point mutations Proteins — enzyme inactivation

25. Free Radical Theory of Aging Aging occurs, in part, from damage caused by reactive oxygen species arising during normal oxidative metabolism

26. Cells are Equipped with Antioxidant Mechanims Superoxide Dismutase Catalase Glutathione Peroxidase Plant-derived Compounds –Ascorbate (vitamin C), α-tocopherol 2 H 2 O 2 — > 2 H 2 O + O 2 2 GSH + H 2 O 2 — > GSSG + 2 H 2 O

27. Oxidative Stress in Aging Buffenstein, R et al; AGE 2008, 30:99-109 ?