Coordination of Intermediary Metabolism

ATP Homeostasis Energy Consumption (adult woman/day) – 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

Glycogenolysis (glycogen metabolism) Glycolysis Citric Acid Cycle Oxidative Phosphorylation

Identification of Potential Control Sites in Electron Transport and Oxidative Phosphorylation

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)

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

Cytochrome c Oxidase Complex IV Irreversible Regulatory Site

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

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

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

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

Figure 17-1 Metabolic Relationships

Figure Regulation of the Citric Acid Cycle Inhibition of ETC  NADH

Coordinate Regulation of Citric Acid Cycle

Coordinate Regulation of Glycolysis and Pyruvate Dehydrogenase Citrate

Inhibition of Phosphofructokinase by Citrate

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

Regulation of Central Metabolic Pathways

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

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

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

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

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

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

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

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

Oxidative Stress in Aging Buffenstein, R et al; AGE 2008, 30: ?