Oxidative Metabolism Energy Flow

• Acetyl-CoA Production: Derived from carbohydrates, fatty acids, and amino acids.

• Acetyl-CoA Oxidation: Occurs in the citric acid cycle.

• Electron Transfer: Establishes proton-motive force and leads to oxidative phosphorylation.

Stages of Oxidative Metabolism

• Location: All stages occur in mitochondria:

  • Stages 1 & 2: Mitochondrial matrix.

  • Stage 3: Inner mitochondrial membrane.

Pyruvate Dehydrogenase Complex

• Function: Oxidizes pyruvate in the presence of oxygen.

  • Net Reaction: Oxidative decarboxylation of pyruvate, where CO2 is released, making it thermodynamically favorable and irreversible.

  • Connects glycolysis to the citric acid cycle by converting pyruvate to acetyl-CoA.

Structure of Pyruvate Dehydrogenase Complex

• Components:

  • Pyruvate dehydrogenase (E1)

  • Dihydrolipoyl transacetylase (E2)

  • Dihydrolipoyl dehydrogenase (E3)

• Coenzymes:

  • Tightly bound (TPP, lipoamide, FAD+) considered prosthetic groups.

  • Mobile carriers (CoA-SH, NAD+).

Regulation of Pyruvate Dehydrogenase

• Activation: Pyruvate, ADP, AMP, CoA, NAD+, Ca2+, Insulin.

• Inhibition: ADP, NADH, acetyl-CoA.

Deficiency of Pyruvate Dehydrogenase Complex

• Lactic Acidosis: Common genetic disorder due to mutations lowering PDH complex activity.

• Consequence:

  • Decreased oxidative metabolism and ATP production.

  • Increased glycolysis (~15x more glucose consumption).

  • Accumulation of lactic and pyruvic acids causing lactic acidosis.

• High ATP Demand Effects: Notable impacts on high ATP demand tissues like the brain, leading to retardation.

Thiamine Pyrophosphate Deficiency

• Condition: Leads to beriberi due to inactive pyruvate dehydrogenase.

  • Central nervous problems from inadequate ATP production.

  • Related to other conditions like Wernicke-Korsakoff syndrome in severe thiamine deficiency due to alcoholism.

Tricarboxylic Acid Cycle (TCA)

• Krebs Cycle: A central metabolic pathway.

• Historical Evidence: Confirmed through experiments involving succinate, fumarate, and malate's effect on oxygen consumption.

Citric Acid Cycle Steps

1. C-C Bond Formation: Acetyl-CoA and oxaloacetate form citrate.

2. Isomerization: Converts citrate to isocitrate.

3. Oxidative Decarboxylation: Produces NADHs, converting isocitrate to ◽α-ketoglutarate.

4. Second Oxidative Decarboxylation: Converts ◽α-ketoglutarate to succinyl-CoA.

5. Substrate-level Phosphorylation: Produces GTP from succinyl-CoA.

6. Oxidation of Succinate: Converts succinate to fumarate.

7. Hydration of Fumarate: Forms malate.

8. Final Oxidation: Oxidizes malate back to oxaloacetate, completing the cycle.

Overview of Citric Acid Cycle

• Energy Yield:

  • 2 carbon atoms enter (from acetyl-CoA) and 2 carbon atoms leave (as CO2).

  • 4 pairs of hydrogen leave through oxidation, reducing 3 NAD+ and 1 FAD.

  • Produces 1 GTP.

• Full Glucose Oxidation: Requires 2 turns of the cycle.

Regulation of the Citric Acid Cycle

• Key Control Points:

  • Controlled at exergonic steps involving citrate synthase, isocitrate dehydrogenase, and α-ketoglutarate dehydrogenase complex.

  • Regulation affected by substrate availability, product inhibition, and intermediates.

• Activation: By ADP, NAD+, and CoA; inhibited by ATP and NADH.

Electron Transport Chain (ETC)

• Function: Transfers electrons through carriers to O2, producing ATP in the process.

• ETC Complexes:

  1. Complex I: NADH to ubiquinone, transported electrons with protons released into the intermembrane space.

  2. Complex II: Succinate to ubiquinone, does not pump protons.

  3. Complex III: Transfers electrons from CoQH2 to cytochrome c.

  4. Complex IV: Reduces oxygen to water using electrons from cytochrome c and pumps additional protons.

ATP Synthesis – Oxidative Phosphorylation

• Chemiosmotic Theory: Proton gradient drives ATP synthesis by ATP synthase.

• ATP Synthase:

  • F0 (proton channel) and F1 (catalytic part), facilitating ADP phosphorylation to ATP.

Regulation of Oxidative Phosphorylation

• Cellular Energy Needs:

  • High energy demand favors ADP and NAD+ activation, low favors ATP and NADH inhibition.

• Inhibitors of Oxidative Phosphorylation:

  1. ATP synthase inhibitors.

  2. ADP/ATP translocase inhibitors.

  3. ETC inhibitors (uncouplers disrupt proton-motive force).

Clinical Correlations

• Coenzyme Q10: Essential for energy metabolism; deficiency linked to heart failure and aging.

• Uncoupling: Important in brown adipose tissue for thermoregulation.

• Mitochondrial Shuttle Systems: For oxidizing cytosolic NADH; include Glycerol 3-P and Malate-Aspartate shuttles.