Leh Chapter 19 Oxidative Phosphorylation(1)

Page 1: Introduction and Key Questions

• Topic: Oxidative Phosphorylation from Lehninger, Chapter 19

• Key Questions:

  • What happens to NADH and FADH2 in various metabolic processes?

  • What is the connection between these molecules and ATP?

  • Source of values 2.5 and 1.5 regarding ATP production.

Page 2: Context for ATP Synthesis

• Metabolic Pathways:- Most ATP is synthesized during fatty acid oxidation and amino acid catabolism under aerobic conditions.

Page 3: Overview of Oxidative Phosphorylation

• Definition: The final stage of cellular respiration.

• Location: Occurs in the mitochondria.

• Key Reactions: Couples oxidation of NADH/FADH2 with reduction of O2 to form H2O and ATP from ADP.

  • Chemical Equation: C6H12O6 + 6 O2 → 6 CO2 + 6 H2O.

• Stages:

  • Stage 1: Acetyl-CoA production via glycolysis and pyruvate dehydrogenase.

  • Stage 2: Acetyl-CoA oxidation in the citric acid cycle, generating NADH and FADH2.

  • Stage 3: Electron transfer and oxidative phosphorylation in the respiratory chain.

Page 4: Mitochondrial Structure and Function

• Components:

  • Outer Membrane: Freely permeable to small molecules, contains porins.

  • Inner Membrane: Impermeable to most small ions, houses:

    • Respiratory electron carriers (Complexes I-IV)

    • ATP synthase and ADP-ATP translocase

  • Matrix: Contains enzymes for various metabolic pathways, DNA, and ribosomes.

• Process Overview:

  1. Electrons flow through a chain of carriers.

  2. Proton movement creates a gradient.

  3. Proton gradient drives ATP synthesis.

Page 5: Respiratory Chain Components

• Structure: Consists of a series of electron carriers organized in complexes.

• Components:

  • Flavoproteins, Hydrophobic quinone (ubiquinone), Cytochromes, Iron-sulfur proteins.

• Function: Involves redox reactions facilitating electron transport.

Page 6: Ubiquinone (Coenzyme Q) in the Respiratory Chain

• Characteristics:

  • Lipid-soluble, capable of accepting 1 or 2 electrons.

  • Transports electrons paired with protons across the membrane.

• Conversion: Reduced to ubiquinol (QH2) after accepting electrons.

Page 7: Cytochromes in the Electron Transport Chain

• Types:

  • Classes a, b, and c, all containing iron.

• Function: Accept one electron per molecule, integral to electron transfer.

Page 8: Iron-Sulfur Proteins

• Role: Participate in one-electron transfers within the respiratory chain, converting iron states during electron transport.

Page 9: Summary of the Respiratory Chain

• Complexes:

  • Four key complexes (I-IV) facilitate proton pumping and electron transfer.

• Process:

  • NADH and succinate contribute electrons to initiate ATP production.

Page 10: Integration of Metabolic Pathways

• Connections: Integrates various metabolic pathways for efficient ATP production.

• Balance among: CAC, fatty acid oxidation, and glycolysis.

Page 11: NADH to FMN Electron Transfer

• Process: NADH donates electrons to FMN, which enters a series of reduction and oxidation steps eventually transferring to ubiquinone.

Page 12: Succinate to Fumarate Conversion

• Mechanism: Succinate oxidized to fumarate, with FAD acting as the electron acceptor.

Page 13: Fatty Acid Electron Transfer in Mitochondria

• Action: Similar to Complex II mechanisms, electrons from fatty acid breakdown reduce ubiquinone.

Page 14: Cytosolic NADH Transport

• Challenge: NADH cannot cross the inner mitochondrial membrane.

• Solution: Use of shuttles (Malate-Aspartate and Glycerol 3-phosphate Shuttles).

Page 15: Detailed Mechanism of the Malate-Aspartate Shuttle

• Process Involvement: Transfers reducing equivalents into the mitochondria through malate and oxaloacetate transformations, coupling with NADH production.

Page 16: Glycerol 3-Phosphate Shuttle

• Function: Shuttles electrons from glycolysis into the mitochondria by converting Glycerol to Glycerol 3-phosphate.

Page 17: Complex III (Cytochrome bc1)

• Coupling Process: Includes cytochrome b and C1 to facilitate electron transfer from ubiquinol to cytochrome c and H+ pumping across the membrane.

Page 18: The Q Cycle in Complex III

• Stages: Sequentially transfers electrons, while pumping H+ into the intermembrane space to maintain the proton gradient.

Page 19: Results of Electron Transfer through Complex III

• Output: Oxidation of QH2, reduction of cytochrome c, and pumping of H+ into the intermembrane space.

Page 20: Electron Transfer to Oxygen

• Final Step: Cytochrome c transfers electrons to cytochrome a and a3, reducing oxygen to produce water while also pumping H+.

Page 21: Importance of Oxygen in Respiration

• Understanding: Oxygen serves as the final electron acceptor in the chain, aiding in water production and maintaining mitochondrial function.

Page 22: Clinical Relevance of Electron Transport

• Implications: Leaky electron transport chain can lead to diseases such as cancer and has microbiological implications in aerobic vs. anaerobic bacteria.

Page 23: Mitochondrial Diseases Overview

• Genetic Basis: Mitochondria have their own genome; diseases include MIDD, LHON, and others.

Page 24: Summary of the Respiratory Chain

• Overall Process: Net transformation of NADH and FADH2 into ATP, water, and CO2 across four mitochondrial complexes.

Page 25: Proton Gradient and Energy Storage

• Concept: Energy from electron transport is converted into a proton gradient, crucial for ATP synthesis.

Page 26: ATP Synthase Mechanism

• Structure: ATP synthase uses the proton gradient to drive ATP production from ADP and P.

Page 27: ATP Synthase Functionality

• Mechanics: Proton-motive force reduces the energy requirement for ATP synthesis, enhancing efficiency.

Page 28: ATP Formation Ratios

• P/O Ratio: Indicates ATP produced per molecule of O2; NADH yields 2.5 ATP and FADH2 yields 1.5 ATP.

Page 29: Efficiency of Oxidative Phosphorylation

• Context: Oxygen dramatically increases ATP production efficiency compared to anaerobic processes such as glycolysis.

Page 30: Regulation of ATP Production

• Dynamics: ATP production is tightly regulated by O2 and ADP levels; changes in [ADP] can significantly alter reaction rates.

Page 31: Interdependency of Processes

• Relationship: Coupling of substrate oxidation, oxygen consumption, and ATP production is vital for cellular respiration.

Page 32: Coupling of Processes

• Significance: Disruption to one process impacts the others; inhibiting electron transfer affects ATP synthesis and vice versa.

Page 33: Consequence of Inhibition in the ETC

• Fork in Pathways: Blocking the electron transport chain increases glucose consumption while decreasing oxygen use.

Page 34: Effects of Specific Inhibitors

• Inhibitors:

  • Rotenone disrupts Complex I.

  • Antimycin A and Cyanide block electron flow similarly.

  • DNP uncouples ATP production from electron transport.

  • Oligomycin blocks ATP synthase function.

Page 35: Uncoupling Effects

• Uncoupler Action: Leads to increased AMP levels and unwanted heat generation rather than ATP production.

Page 36: Historical Context of Uncoupling Agents

• DNP as a Drug: Increased metabolic rates led to weight loss, but also posed risks of hyperthermia.

Page 37: Benefits of Uncoupling in Specific Tissues

• Target: Brown adipose tissue (BAT) generates heat instead of ATP, crucial for thermoregulation in newborns.

Page 38: Transport Processes Driven by the Proton Gradient

• Key Functions: Proton gradient facilitates transport of ADP, ATP, and phosphate into and out of the mitochondria via specific translocases.

Page 39: Final Overview of Respiratory Dynamics

• Summary Flow: Comprehensive overview of electron transport from NADH to ATP production intertwined with physiological relevance of each step.

Oxidative Phosphorylation from Lehninger, Chapter 19

Introduction and Key Questions

• Topic: Oxidative Phosphorylation

• Key Questions:

  • What happens to NADH and FADH2 during various metabolic processes and how are they utilized in ATP generation?

  • What is the connection between these electron carriers and ATP synthesis?

  • What are the sources of the values 2.5 and 1.5 regarding ATP production from NADH and FADH2, respectively?

Context for ATP Synthesis

• Metabolic Pathways:

  • The majority of ATP is synthesized during the processes of fatty acid oxidation and amino acid catabolism, particularly under aerobic conditions where oxygen is present, maximizing energy yield.

Overview of Oxidative Phosphorylation

• Definition:

  • The final and critical stage of cellular respiration, characterized by the phosphorylation of ADP to form ATP as electrons are transferred through the electron transport chain.

• Location:

  • Occurs in the mitochondria, specifically across the inner mitochondrial membrane.

• Key Reactions:

  • Couples the oxidation of NADH and FADH2 with the reduction of molecular oxygen (O2) to produce water (H2O) and synthesize ATP from ADP and inorganic phosphate (Pi).

• Chemical Equation:

  • [ C_6H_{12}O_6 + 6 O_2 \rightarrow 6 CO_2 + 6 H_2O ]

• Stages of Oxidative Phosphorylation:

  • Stage 1: Acetyl-CoA production through glycolysis and the pyruvate dehydrogenase complex, converting 3-carbon pyruvate into 2-carbon acetyl-CoA.

  • Stage 2: Oxidation of Acetyl-CoA within the citric acid cycle, resulting in the generation of reduced cofactors NADH and FADH2 along with ATP (or GTP).

  • Stage 3: Electron transfer process leading to oxidative phosphorylation via the respiratory chain, where high-energy electrons are transferred through various complexes chiefly utilizing the energy to pump protons and generate a proton gradient.

Mitochondrial Structure and Function

• Components:

  • Outer Membrane:

    • Freely permeable to small molecules and ions, contains transmembrane proteins called porins, allowing the passage of metabolites.

  • Inner Membrane:

    • Impermeable to most small ions, it houses essential components such as:

      • Respiratory electron carriers (Complexes I-IV) which facilitate electron transport and proton pumping.

      • ATP synthase, the enzyme responsible for synthesizing ATP from ADP and Pi.

      • ADP-ATP translocase, which transports ATP out of the mitochondria and imports ADP.

  • Matrix:

    • Contains enzymes crucial for various metabolic pathways like the citric acid cycle, along with mitochondrial DNA and ribosomes, supporting the organelle's own protein synthesis.

• Process Overview:

  • The flow of electrons through a chain of carriers is coupled with proton movement across the inner membrane, creating a proton gradient that drives ATP synthesis through ATP synthase.

Summary

This expanded overview highlights critical aspects of oxidative phosphorylation by elucidating elements such as the sources of ATP, the mechanisms involved in electron transport and proton gradient generation, and the intricate structure and function of mitochondria as the site of ATP production.

Objectives and Questions

1. What happens to NADH and FADH2 during various metabolic processes and how are they utilized in ATP generation?

   • Answer: NADH and FADH2 are produced during glycolysis and the citric acid cycle. They serve as electron carriers in the electron transport chain, where they donate electrons leading to the production of ATP through oxidative phosphorylation. NADH generally yields more ATP than FADH2 because it contributes to more proton pumping across the inner mitochondrial membrane.

2. What is the connection between these electron carriers and ATP synthesis?

   • Answer: NADH and FADH2 are crucial for ATP synthesis as they are oxidized in the electron transport chain. The electrons transferred from these carriers are used to pump protons out of the mitochondrial matrix, creating a proton gradient. This gradient is then used by ATP synthase to convert ADP and inorganic phosphate (Pi) into ATP.

3. What are the sources of the values 2.5 and 1.5 regarding ATP production from NADH and FADH2, respectively?

   • Answer: The values 2.5 and 1.5 refer to the number of ATP molecules produced per molecule of NADH and FADH2, respectively, during oxidative phosphorylation. These values are derived from the energy yield accounting for the proton gradient developed during electron transport, with NADH contributing to three proton pumping events per molecule and FADH2 contributing to two.