4.3: Electron transport chain (ETC)

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In the production of NADH and FADH\(_2\) by the TCA cycle, \(\beta\)-oxidation or glycolysis is funneled directly into the electron transport chain (ETC) where each of these reduced coenzymes will donate two electrons to electron carriers. As the electrons are passed down their oxidation gradient, some of the energy is lost, but much of this energy is used to pump protons into the intermembrane space of the mitochondria.

The process of oxidative phosphorylation (figure 4.14) involves the coupling of electron transfer with the pumping of protons to generate an electrochemical gradient across the mitochondrial membrane. With the exception of CoQ all proteins are bound to the mitochondria membrane, and electrons are passed between metal containing cytochromes. Complex I and Complex II function in parallel (rather than series) with each other having preference for NADH or FADH\(_2\), respectively. Complex II (succinate dehydrogenase) is not required for oxidative phosphorylation because it does not span the mitochondrial membrane (figure 4.14). Electrons are passed down an electrochemical gradient, and molecular oxygen is the final electron acceptor (molecular oxygen).

There are site specific inhibitors of the ETC to be aware of, and these will disrupt electron flow reducing overall ATP production.

Membrane separating the mitochondrial matrix (top) and inner membrane space (bottom). From left to right, NADH dehydrogenase (Complex I) 4H+ moving down, NADH right arrow NAD+, 2e- arrow CoQ. Succinate dehydrogenase (Complex II) FAD/FADH2 cycle and 2e- right arrow cytochrome c complex. CoQ. Cytochrome c reductase (Complex III) 4H+ moving down. Cyt C. Cytochrome c oxidase (Complex IV) 2H+ moving down, ½ O2 + 2H+ right arrow H2O. ATP synthase (complex V) 3H+ moving up, ADP+Pi right arrow ATP. Phosphate transporter Pi moves up. Adenine nucleotide transporter ADP moves up and ATP moves down. — Figure 4.14: Overview of the electron transport chain (ETC).

Inhibitors

Inhibitors block oxidation and reduce both ATP generation and oxygen consumption; this is in contrast to uncouplers, which disrupt the mitochondrial membrane and reduce ATP production but increase oxygen consumption.

A common inhibitor of the ETC is carbon monoxide; this will bind to Complex IV and therefore halt the passing of electrons. Without electrons passing through the complexes, the pumping of protons is diminished and ATP is not produced. Other common inhibitors are cyanide (Complex IV), rotenone (Complex I), antimycin C (Complex III), and oligomycin, which is a Complex V inhibitor.

Uncouplers

Uncoupling of the ETC by the addition of agents such as dinitrophenol have different consequences. Uncouplers disrupt the permeability of the inner membrane (either physically or chemically) and dissipate the proton gradient.

In these cases, the release of protons across the membrane is coupled with the release of heat, rather than harnessed in the form of a phosphate bond. NADH oxidation continues rapidly, oxygen consumption is increased, and ATP production decreases. Valinomycin is another common uncoupler.

Biological uncoupling through the expression of uncoupling proteins (UPC) is also likely. These proteins form a physical pore within the mitochondrial membrane allowing the proton gradient to equilibrate. In brown fat, this nonshivering thermogenesis is a means of generating heat, and other members of this protein family (UPC) are expressed in various tissues but have similar roles.

References and resources

Text

Ferrier, D. R., ed. Lippincott Illustrated Reviews: Biochemistry, 7th ed. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins, 2017, Chapter 6: Bioenergetics and Oxidative Phosphorylation: Section V, VI, Chapter 8: Introduction to Metabolism and Glycolysis, Chapter 9: TCA Cycle and Pyruvate Dehydrogenase Complex: Section IIA, IIB, Chapter 11: Glycogen Metabolism: Section V, VI, Chapter 16: Fatty Acid Ketone Body and TAG Metabolism: Section II, IV, V, Chapter 23: Metabolic Effect of Insulin and Glucagon, Chapter 25: Diabetes Mellitus.

Le, T., and V. Bhushan. First Aid for the USMLE Step 1, 29th ed. New York: McGraw Hill Education, 2018, 72–78, 85–89.

Lieberman, M., and A. Peet, eds. Marks' Basic Medical Biochemistry: A Clinical Approach, 5th ed. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins, 2018, Chapter 2: The Fed or Absorptive State, Chapter 19: Basic Concepts of Regulation: Section IV.A.1.2, Chapter 20: Cellular Bioenergetics, Chapter 22: Generation of ATP from Glucose: Section I.A.B.C, III, Chapter 24: Oxidative Phosphorylation and the ETC: Section I.E, II, III, Chapter 31: Synthesis of Fatty Acids: Section I.A.B, IV, V.

Figures

Grey, Kindred, Figure 4.14 Overview of the electron transport chain (ETC). 2021. https://archive.org/details/4.14_20210924. CC BY 4.0.