Electron Transport Chain (ETC)

The electron transport chain (ETC) sends electrons through a series of proteins, which generate an electrochemical proton gradient that produces energy in the form of adenosine triphosphate (ATP). Proteins generate energy through redox reactions that create the proton gradient. The complete aerobic catabolism of 1 molecule of glucose yields between 36 and 38 ATPs, mostly through energy obtained as the reduced coenzymes NADH and FADH2 are conveyed through the electron transport system. Three of the 4 respiratory complexes that make up the mitochondrial respiratory chain, as well as ATP synthase, are embedded in the inner mitochondrial membrane. Coenzyme Q and cytochrome c transfer electrons between complexes, which will ultimately meet oxygen and generate H2O.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Table of Contents

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Structure of Mitochondria

  • Mitochondria: 
    • Double-membraned organelles Organelles A cell is a complex unit that performs several complex functions. An organelle is a specialized subunit within a cell that fulfills a specific role or function. Organelles are enclosed within their own lipid bilayers or are unbound by membranes. The Cell: Organelles 
    • Generate energy for the cell in the form of adenosine triphosphate (ATP)
    • Provide important signals for the body and assist in cell differentiation and cell death Cell death Injurious stimuli trigger the process of cellular adaptation, whereby cells respond to withstand the harmful changes in their environment. Overwhelmed adaptive mechanisms lead to cell injury. Mild stimuli produce reversible injury. If the stimulus is severe or persistent, injury becomes irreversible. Apoptosis is programmed cell death, a mechanism with both physiologic and pathologic effects. Cell Injury and Death 
  • Inner and outer membranes surround mitochondria:
    • Made up of a phospholipid bilayer and protein
    • Inner membrane: 
      • Houses proteins that generate reactions necessary for the ETC (e.g., ATP synthase).
      • Possesses invaginations called cristae, which house respiratory complexes
      • Cristae are infoldings that increase the surface area of the inner membrane and effectively increase the respiratory capability of mitochondria.
      • The inner membrane is permeable to O2, CO2, and H2O only.
    • Matrix: space within the inner membrane
      • Home to important proteins: enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes and intermediates of the citric acid cycle Citric acid cycle The citric acid cycle, also known as the tricarboxylic acid (TCA) cycle or the Krebs cycle, is a cyclic set of reactions that occurs in the mitochondrial matrix. The TCA cycle is the continuation of any metabolic pathway that produces pyruvate, which is converted into its main substrate, acetyl-CoA. Citric Acid Cycle and oxidation of pyruvate
      • Contains the mitochondrial DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure genome
      • ADP and inorganic phosphate (Pi) are specifically transported into the matrix as newly synthesized ATP is transported out.
    • Outer membrane: contains porins that permit diffusion of ions and metabolites
      • Passage of metabolites, such as ATP, ADP, calcium ion (Ca2+), and phosphate is a process mediated by transport proteins:
        • Stores voltage-dependent anion channels, which allow for the transit of nucleotides and ions
        • Permits the generation of ion gradients
      • Specific transporters carry pyruvate, fatty acids Fatty acids Fatty acids are integral building blocks of lipids, and can be classified as unsaturated or saturated based on the presence/absence of carbon-carbon double bonds within their nonpolar chains. Fatty Acids and Lipids, and amino acids or their alpha-keto derivatives into the matrix for access to the machinery of the citric acid cycle Citric acid cycle The citric acid cycle, also known as the tricarboxylic acid (TCA) cycle or the Krebs cycle, is a cyclic set of reactions that occurs in the mitochondrial matrix. The TCA cycle is the continuation of any metabolic pathway that produces pyruvate, which is converted into its main substrate, acetyl-CoA. Citric Acid Cycle.
    • Intermembrane space: between the outer and inner membranes
      • Contains the same small molecules that are present in the cytosol
      • Controlled region with different larger proteins that are regulated by the outer membrane
Anatomy of mitochondrion

Anatomy of the mitochondrion:
The important structures of the mitochondrion include the outer membrane, intermembrane space, inner membrane, and matrix.

Image by Lecturio.

Complexes of the ETC

Complex I

  • NADH:ubiquinone oxidoreductase
  • The enzyme complex moves 2 electrons from NADH to a carrier (ubiquinone) through a redox reaction that translocates 4 protons.
  • The protons are pumped from the matrix to the intermembrane space.

Complex II

  • Succinate dehydrogenase
  • Delivers electrons for the quinone pool
  • Transfers FAD to quinone

Complex III

  • Coenzyme Q-cytochrome c reductase
  • 4 protons translocated to the intermembrane space
  • Complex inhibited by dimercaprol

Complex IV

  • Cytochrome c oxidase
  • 4 electrons transfer to O2 and produce 2 molecules of H2O.
  • 8 protons added to the proton gradient 

Electron Transport

  • Inner mitochondrial membrane:
    • Mostly impermeable to molecules and ions such as hydrogen ions (H+)
    • Separates the intermediates and enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes of metabolic pathways of those in the cytosol Cytosol A cell's cytoskeleton is a network of intracellular protein fibers that provides structural support, anchors organelles, and aids intra- and extracellular movement. . The Cell: Cytosol and Cytoskeletonfrom those occurring in the mitochondrial matrix
    • Plays host to cofactors that were reduced throughout catabolic pathways occurring in different cellular compartments
    • Bears the compartment of the respiratory chain and ATP synthase
  • Mitochondrial matrix:
    • Contains the pyruvate dehydrogenase complex enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes 
    • Also contains the citric acid cycle Citric acid cycle The citric acid cycle, also known as the tricarboxylic acid (TCA) cycle or the Krebs cycle, is a cyclic set of reactions that occurs in the mitochondrial matrix. The TCA cycle is the continuation of any metabolic pathway that produces pyruvate, which is converted into its main substrate, acetyl-CoA. Citric Acid Cycle enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes, the fatty acid beta-oxidation pathway, and other pathways involved in amino acid Amino acid Amino acids (AAs) are composed of a central carbon atom attached to a carboxyl group, an amino group, a hydrogen atom, and a side chain (R group). Basics of Amino Acids oxidation
  • Here, the conveying of electrons through 3 respiratory complexes is coupled to the outward pumping of protons.
Mitochondrial membranes

Mitochondrial membranes:
Key proteins are shown within the inner membrane. The citric acid cycle Citric acid cycle The citric acid cycle, also known as the tricarboxylic acid (TCA) cycle or the Krebs cycle, is a cyclic set of reactions that occurs in the mitochondrial matrix. The TCA cycle is the continuation of any metabolic pathway that produces pyruvate, which is converted into its main substrate, acetyl-CoA. Citric Acid Cycle is crucial to the process, as it provides NADH for the electron transport chain (ETC).

Image: “Mitochondrial electron transport chain—Etc4” by Fvasconcellos. License: Public Domain

Oxidative Phosphorylation

  • The ETC is linked to oxidative phosphorylation through the proton gradient.
  • ATP synthase harnesses the proton gradient through oxidative phosphorylation to generate ATP:
    • ATP synthase functions as an ion channel for protons to return to the mitochondrial matrix.
    • Energy is generated by the flow Flow Blood flows through the heart, arteries, capillaries, and veins in a closed, continuous circuit. Flow is the movement of volume per unit of time. Flow is affected by the pressure gradient and the resistance fluid encounters between 2 points. Vascular resistance is the opposition to flow, which is caused primarily by blood friction against vessel walls. Vascular Resistance, Flow, and Mean Arterial Pressure of protons, which is used for ATP synthesis.
  • There are numerous ways to generate ATP: 
    • Glycolysis Glycolysis Glycolysis is a central metabolic pathway responsible for the breakdown of glucose and plays a vital role in generating free energy for the cell and metabolites for further oxidative degradation. Glucose primarily becomes available in the blood as a result of glycogen breakdown or from its synthesis from noncarbohydrate precursors (gluconeogenesis) and is imported into cells by specific transport proteins. Glycolysis:
      • 2 ATP are produced during glycolysis.
      • 2 NAD+ are reduced to NADH.
      • 2 pyruvate molecules are then used to produce 2 Acetyl-CoA molecules by pyruvate dehydrogenase, which produces 1 NADH each.
      • 2 Acetyl-CoA molecules enter the citric acid cycle Citric acid cycle The citric acid cycle, also known as the tricarboxylic acid (TCA) cycle or the Krebs cycle, is a cyclic set of reactions that occurs in the mitochondrial matrix. The TCA cycle is the continuation of any metabolic pathway that produces pyruvate, which is converted into its main substrate, acetyl-CoA. Citric Acid Cycle, where they condense with oxaloacetate and generate:
        • 2 guanosine triphosphates (GTP), which are converted to 2 ATPs
        • 6 NADH
        • 2 FADH2
  • The ETC is crucial for setting up the proton gradient:
    • Each NADH enters the electron transport chain at complex I, where it is reoxidized and passes its electrons to CoQ.
    • Electrons flow Flow Blood flows through the heart, arteries, capillaries, and veins in a closed, continuous circuit. Flow is the movement of volume per unit of time. Flow is affected by the pressure gradient and the resistance fluid encounters between 2 points. Vascular resistance is the opposition to flow, which is caused primarily by blood friction against vessel walls. Vascular Resistance, Flow, and Mean Arterial Pressure from CoQ to complex III, which relays them through cytochrome c to complex IV.
    • Here, they are accepted by O2.
    • Both complex I and complex IV convey 4 protons each into the intermembrane space, whereas complex III pumps 2.
    • 6 NADH produced during the citric acid cycle Citric acid cycle The citric acid cycle, also known as the tricarboxylic acid (TCA) cycle or the Krebs cycle, is a cyclic set of reactions that occurs in the mitochondrial matrix. The TCA cycle is the continuation of any metabolic pathway that produces pyruvate, which is converted into its main substrate, acetyl-CoA. Citric Acid Cycle yield 60 protons in the intermembrane space.
  • 2 ATP generated during glycolysis and 2 produced in the citric acid cycle Citric acid cycle The citric acid cycle, also known as the tricarboxylic acid (TCA) cycle or the Krebs cycle, is a cyclic set of reactions that occurs in the mitochondrial matrix. The TCA cycle is the continuation of any metabolic pathway that produces pyruvate, which is converted into its main substrate, acetyl-CoA. Citric Acid Cycle
Table: Protons conveyed into the intermembrane space as a result of oxidation of 1 molecule of palmitoyl-CoA to CO2 and H2
Enzyme catalyzing oxidation step Number of NADH or FADH2 formed Number of protons ultimately translocated into intermembrane space
Acyl-CoA dehydrogenase 7 FADH2 42
Beta-hydroxyacyl-CoA dehydrogenase 7 NADH 70
Isocitrate dehydrogenase 8 NADH 80
Alpha-ketoglutarate dehydrogenase 8 NADH 80
Succinate dehydrogenase 8 FADH2 48
Malate dehydrogenase 8 NADH 80
Total 400

Control of Oxidative Phosphorylation

  • Important regulation mechanisms exist to control the rate of glycolysis, the citric acid cycle Citric acid cycle The citric acid cycle, also known as the tricarboxylic acid (TCA) cycle or the Krebs cycle, is a cyclic set of reactions that occurs in the mitochondrial matrix. The TCA cycle is the continuation of any metabolic pathway that produces pyruvate, which is converted into its main substrate, acetyl-CoA. Citric Acid Cycle, pyruvate oxidation, and oxidative phosphorylation by the relative concentrations: 
    • ATP
    • ADP
    • AMP
    • NADH
  • Glycolysis Glycolysis Glycolysis is a central metabolic pathway responsible for the breakdown of glucose and plays a vital role in generating free energy for the cell and metabolites for further oxidative degradation. Glucose primarily becomes available in the blood as a result of glycogen breakdown or from its synthesis from noncarbohydrate precursors (gluconeogenesis) and is imported into cells by specific transport proteins. Glycolysis, fatty acid degradation, and the citric acid cycle Citric acid cycle The citric acid cycle, also known as the tricarboxylic acid (TCA) cycle or the Krebs cycle, is a cyclic set of reactions that occurs in the mitochondrial matrix. The TCA cycle is the continuation of any metabolic pathway that produces pyruvate, which is converted into its main substrate, acetyl-CoA. Citric Acid Cycle provide the primary sources of electrons that enter the mitochondrial ETC.
  • Control of glycolysis and the citric acid cycle Citric acid cycle The citric acid cycle, also known as the tricarboxylic acid (TCA) cycle or the Krebs cycle, is a cyclic set of reactions that occurs in the mitochondrial matrix. The TCA cycle is the continuation of any metabolic pathway that produces pyruvate, which is converted into its main substrate, acetyl-CoA. Citric Acid Cycle is coordinated with the demand for oxidative phosphorylation.
  • Oxidative phosphorylation is maintained by cellular energy requirements:
    • Intracellular ADP and the ATP are measures of a cell’s energy status.
    • An adequate supply of electrons to feed the electron transport chain is provided by regulation of the control points of glycolysis and the citric acid cycle Citric acid cycle The citric acid cycle, also known as the tricarboxylic acid (TCA) cycle or the Krebs cycle, is a cyclic set of reactions that occurs in the mitochondrial matrix. The TCA cycle is the continuation of any metabolic pathway that produces pyruvate, which is converted into its main substrate, acetyl-CoA. Citric Acid Cycle by NADH and metabolites:
      • Phosphofructokinase (PFK)
      • Pyruvate dehydrogenase
      • Citrate synthase
      • Isocitrate dehydrogenase (IDH)
      • Alpha-ketoglutarate dehydrogenase
  • Interlocking of the citric acid cycle Citric acid cycle The citric acid cycle, also known as the tricarboxylic acid (TCA) cycle or the Krebs cycle, is a cyclic set of reactions that occurs in the mitochondrial matrix. The TCA cycle is the continuation of any metabolic pathway that produces pyruvate, which is converted into its main substrate, acetyl-CoA. Citric Acid Cycle and glycolysis by citrate, which hinders glycolysis, facilitates the mode of action of the adenine nucleotide system:
    • Increased levels of NADH and acetyl-CoA hinders the oxidation of pyruvate to acetyl-CoA.
    • A high NADH/NAD+ ratio hinders the dehydrogenase reactions of the citric acid cycle Citric acid cycle The citric acid cycle, also known as the tricarboxylic acid (TCA) cycle or the Krebs cycle, is a cyclic set of reactions that occurs in the mitochondrial matrix. The TCA cycle is the continuation of any metabolic pathway that produces pyruvate, which is converted into its main substrate, acetyl-CoA. Citric Acid Cycle.
  • Another important regulatory effect is the inhibition of PFK by citrate:
    • When the demand for ATP decreases, ATP increases and ADP decreases.
    • Because ADP activates IDH and ATP inhibits alpha-ketoglutarate dehydrogenase, the citric acid cycle Citric acid cycle The citric acid cycle, also known as the tricarboxylic acid (TCA) cycle or the Krebs cycle, is a cyclic set of reactions that occurs in the mitochondrial matrix. The TCA cycle is the continuation of any metabolic pathway that produces pyruvate, which is converted into its main substrate, acetyl-CoA. Citric Acid Cycle slows down.
    • The slow-down causes the citrate concentration to build up.
    • Citrate leaves the mitochondria via a specific transport system and, once in the cytosol, acts to restrain carbohydrate breakdown by inhibiting PFK.

References

  1. Ahmad, M, Woiberg, A, Kahwaji, CI. (2020). Biochemistry, electron transport chain. StatPearls. Retrieved May 26, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK526105/
  2. Cooper, GM. (2000). The mechanism of oxidative phosphorylation. The Cell: A Molecular Approach. 2nd edition. Sunderland (MA): Sinauer Associates. https://www.ncbi.nlm.nih.gov/books/NBK9885/
  3. Alberts, B, Johnson, A, Lewis, J, et al. (2002). Electron-transport chains and their proton pumps. Molecular Biology of the Cell. 4th edition. New York: Garland Science. https://www.ncbi.nlm.nih.gov/books/NBK26904/

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