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Coordination of Intermediary Metabolism. 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. Strict Coordinate Control.
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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
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 (Fe3+) + ADP + Pi——> 1/2 NAD+ + Cytochrome c (Fe2+) + ATP ∆G’ = ~0 (reversible)
Complex I and III Equilibrium ATP Mass Action Ratio (compare with Energy Charge)
Cytochrome c OxidaseComplex 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 Ca2+ • IF1: inhibitor of F1–ATPase
IF1(Inhibitor of F1–ATPase) Inactive during active respiration Traps ATP bound to DP Prevents ATPase activity when [O2] is low
Sources of Electrons for Mitochondrial Electron Transport • Glycolysis (or glycogenolysis) • Fatty acid degradation • Citric Acid Cycle • Amino acid degradation
Metabolic Relationships Figure 17-1
Regulation of the Citric Acid CycleInhibition of ETC NADH Figure 17-16
Coordinate Regulation of Glycolysis and Pyruvate Dehydrogenase 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
Advantages of Aerobic Metabolism Anaerobic glycolysis: 2 ATP C6H12O6 + 2 ADP + 2 Pi—> 2 Lactate + 2 H+ + 2 H2O + 2 ATP Aerobic metabolism of glucose: 32 ATP C6H12O6 + 32 ADP + 32 Pi + 6 O2—> 6 CO2 + 38 H2O + 32 ATP
Drawbacks or Disadvantages of Aerobic Metabolism Sensitivity to O2 Deprivation Production of Reactive Oxygen Species (ROS)
Oxygen Deprivation inHeart Attack and Stroke Myocardial Infarction: interuption of the blood (O2) supply to a portion of the heart Stroke: interuption of the blood (O2) supply to a portion of the brain
Consequences of O2 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 H2O2—> 2 H2O + O2 2 GSH + H2O2—> GSSG + 2 H2O
Oxidative Stress in Aging ? Buffenstein, R et al; AGE 2008, 30:99-109