Cellular Energy Production and Oxygen

Role of Oxygen in Energy Production

• Oxygen is crucial for extracting energy from major nutrients.
• Cells absorb oxygen and nutrients, and mitochondria further use nutrient metabolites and oxygen.
• Cytochromes are oxygen-binding proteins.
• Electrons from nutrient metabolites are transferred to mobile carriers.
• Cytochrome Oxidase binds and reduces oxygen.
• Oxygen reduction is vital for ATP synthesis.

Stages in Extracting Energy

• Energy extraction from nutrients involves three stages:
  • Stage I: Digestion, absorption, transport
  • Stage II: Breakdown of small molecules into key metabolites
  • Stage III: Complete transfer of energy to a usable form for cells
• The process involves fats, polysaccharides, and proteins as fuel molecules.
• These macronutrients are converted to smaller molecules like Acetyl CoA.

Reactions Requiring Oxygen

• Oxygen acts as an electron sink in energy generation.
• It extracts high-potential electrons from NADH and FADH2, which are generated by oxidizing carbohydrates, amino acids, and fatty acids.
• Oxygen is also involved in the biosynthesis of steroids and biodegradation of drugs/toxins.

Metabolism of Major Nutrients and Energy Extraction

• Nutrient metabolism starts in the cytoplasm.
• Glucose and amino acids are converted.

Role of Mitochondria

• Mitochondria are crucial in ATP production.
• Oxidative phosphorylation is the process where mitochondria produce ATP by transferring electrons from NADH or FADH2 to oxygen.

Oxidative Phosphorylation in Eukaryotes

• Oxidative phosphorylation relies on protein complexes located in the inner mitochondrial membrane.
• These complexes, including the electron transport chain and ATP synthase, are located in the inner membrane.
• Oxygen accepts the energy-depleted electrons and combines with hydrogen atoms to form water.

Flow of Electrons

• The flow of electrons from NADH or FADH2 to oxygen triggers the pumping of protons outside the mitochondrial matrix.
• This creates a pH gradient that helps generate ATP (Chemiosmotic hypothesis).

Components of the Electron Transport Chain

• The electron transport chain (ETC) includes 3 oxido-reductase complexes that function as proton pumps (I, III, and IV).
• These complexes use NADH-Q reductase, cytochrome reductase, and cytochrome oxidase.
• Two electron carriers, ubiquinone (Q) and cytochrome c, are also involved.

Driving Force for Oxidative Phosphorylation

• The driving force behind oxidative phosphorylation is the transfer potential of NADH or FADH2 relative to oxygen.
• The oxidation of NADH or FADH2 provides the energy to synthesize ATP.
• Each ATP molecule requires approximately 7.3 kcal

NADH-Q Reductase (Complex I)

• This complex consists of 34 polypeptides, and has FMN and Fe-S prosthetic groups.
• The flow of two electrons from NADH to QH2 through NADH-Q reductase pumps 4 protons from the matrix to the cytosol side of the inner membrane.

Coenzyme Q (Ubiquinone)

• It's a quinone derivative with a long isoprenoid tail, which functions as an electron carrier.
• It exists in three forms: oxidized (Q), semiquinone intermediate (Q*), and reduced (QH2).

Succinate-Q Reductase (Complex II)

• Coenzyme Q also receives electrons from FADH2.
• Electrons from FADH2 are transferred to Complex II and then to Q to enter the ETC.
• Unlike complexes I, III, and IV, Complex II is not a proton pump.

Cytochrome Reductase (Complex III) and Cytochrome C

• Electrons flow from ubiquinone (Q) to Complex III and then to cytochrome c,
• Two (2) protons are pumped out into the cytosol.
• Cytochrome c is an electron carrier protein with heme.

Haeme (Heme) Structure

• Heme is a crucial part of cytochrome c, acting as an electron donor/acceptor in cytochromes.
• It's also involved in oxygen binding in hemoglobin and cytochrome oxidase

Cytochrome Oxidase (Complex IV)

• Cytochrome c transfers electrons to oxygen.
• Complex IV catalyzes the transfer of electrons from cytochrome c to oxygen.
• Four protons are pumped out to the cytosol during this process.

Inhibitors of Electron Transfer

• Inhibitors like rotenone, amytal, and antimycin A block the ETC, preventing electron flow.
• Cyanide, N3, and CO inhibit cytochrome oxidase (complex IV).

Chemiosmotic Hypothesis

• Electron transfer through the respiratory chain pumps protons from the matrix to the cytosol.
• This generates a proton-motive force.
• This force drives ATP synthesis by ATPase in the mitochondria.

ATP Synthase

• ATP synthase is an enzyme complex, composed of proton-conducting Fo and a catalytic F1 units.
• The Fo containing stalk has several proteins to increase sensitivity to oligomycin.

Action of ATP Synthase

• Proton flux through ATP synthase cause conformation changes in the enzyme for ATP formation.
• translocation of three (3) protons through the synthase leads to the formation of one ATP.

ATP-ADP Translocase

• The entry of ADP into mitochondria depends on ATP exit via ATP-ADP translocase.
• It cost 1 proton to drive the transport of ATP in/out of mitochondria.
• About 25% of energy from electron transfer is used for ATP transport

Energy Yield in Electron Transfer

• NADH-Q reductase pumps (4) protons.
• Cytochrome reductase pumps (2).
• Cytochrome oxidase pumps (4).
• Synthesis of 1 ATP needs 3 protons.
• Flow of 2 electrons from NADH to O2 leads to 10 protons pumped and generate 2.5 cytosolic ATP.
• Flow of 2 electrons from FADH2 to O2 leads to 6 protons pumped and generate about 1.5 cytosolic ATP.

ATP Yield from Complete Glucose Oxidation

• Glycolysis gives about 2 ATP and 2 NADH
• Converting 2 pyruvate into 2 acetyl CoA gives 2 NADH, and 2GTP
• The Krebs Cycle (TCA cycle) gives 6NADH, 2FADH2, and 2GTP.

Two Shuttle Systems for NADH

• Glycerol 3-phosphate shuttle transfers electrons from NADH to FADH2.
• Malate-aspartate shuttle transfers electrons from NADH to NADH, retaining the reducing potential.

Uncoupling of Oxidative Phosphorylation

• Uncouplers like DNP disrupt the coupling between electron transport and ATP synthesis by carrying protons across the membrane.
• This dissipates the proton motive force.
• Uncoupling increases oxidation and oxygen consumption.

Uncoupling and Thermogenesis

• Uncoupling is a way to generate heat to maintain body temperature in hibernating animals, newborns, and cold-adapted mammals.
• Brown adipose tissue, rich in mitochondria, uses uncoupling protein UCP-1 to dissipate the proton gradient and create heat.

UCP-1 and Thermogenesis

• UCP-1 carries protons across the inner mitochondrial membrane, leading to thermogenesis.
• Sympathetic nerve stimulation triggers the formation of free fatty acids, activating UCP-1 and creating heat.

Cyanide Poisoning

• Cyanide inhibits oxidative phosphorylation by blocking cytochrome oxidase.

Opisthotonus in Tetanus

• Opisthotonus is a symptom of tetanus characterized by spasm of axial muscles, causing the head, neck, and spinal column to arch backwards.

Cyanide Poisoning: Treatment

• General supportive care and oxygen.
• GI decontamination methods to remove toxins.
• Conversion of hemoglobin Fe2 to Fe3 can release cyanide from cytochrome oxidase and encourage metabolism of cyanide to thiocyanate.
• Thiosulfate is used to catalyze the conversion of cyanide to less harmful thiocyanate.

Mitochondria as a Source of Chemical Signals

• Mitochondria release cytochrome c, triggering apoptosis (programmed cell death).
• Problems with ETC enzymes can cause neurodegenerative disorders like Parkinson's disease.
• Mitochondria produce reactive oxygen species, potentially contributing to aging and metabolic syndromes.

Summary of Energy Extraction

• Optimal energy extraction from nutrients relies on oxygen.
• Blood circulation delivers oxygen and nutrients.
• Mitochondria synthesize ATP using oxidative phosphorylation.
• Electron release from nutrients drives proton pumping.
• Proton gradient drives ATP synthesis, which is done by mobile proton carriers.
• Complexes I and II provide connections between the Krebs cycle and the ETC.