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The Electron Transport Chain: Powerhouse of Cellular Energy

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The electron transport chain (ETC) stands as a pivotal biochemical pathway, orchestrating a series of redox reactions to forge an electrochemical gradient. This gradient is the driving force behind ATP synthase, culminating in the production of ATP through oxidative phosphorylation. This remarkable process unfolds within the mitochondria during cellular respiration and within chloroplasts during photosynthesis. In cellular respiration, the ETC harnesses electrons liberated from the breakdown of nutrient molecules to generate energy. Conversely, in photosynthesis, light-energized electrons enter the chain, channeling captured solar energy into the synthesis of carbohydrates.

Unveiling the Fundamentals of the Electron Transport Chain

Aerobic cellular respiration, the cornerstone of energy production in many organisms, is a meticulously orchestrated three-stage process: glycolysis, the citric acid cycle (Krebs cycle), and oxidative phosphorylation. Glycolysis initiates the breakdown of glucose into two pyruvate molecules, yielding a modest ATP output and the crucial electron carrier, nicotinamide adenine dinucleotide (NADH). Each pyruvate then undergoes oxidation to acetyl CoA, accompanied by the generation of another NADH molecule and carbon dioxide (CO2). Acetyl CoA fuels the citric acid cycle, a cascade of chemical reactions that further produce CO2, NADH, flavin adenine dinucleotide (FADH2), and a small amount of ATP. The grand finale, oxidative phosphorylation, harnesses the NADH and FADH2 generated in the preceding stages to synthesize water and substantial amounts of ATP.

Oxidative phosphorylation itself is a two-pronged process, comprising the electron transport chain (ETC) and chemiosmosis. The ETC is an assembly of proteins and organic molecules embedded within the inner mitochondrial membrane. Electrons cascade through this chain in a series of redox reactions, progressively releasing energy. This liberated energy is skillfully channeled to establish a proton gradient across the inner mitochondrial membrane. Chemiosmosis then capitalizes on this proton gradient, employing the ATP synthase protein to drive the synthesis of copious amounts of ATP.

Photosynthesis, the remarkable process that sustains life on Earth, converts light energy into chemical energy to construct sugars. The light-dependent reactions of photosynthesis utilize light energy and water to generate ATP, NADPH, and oxygen (O2). Crucially, an electron transport chain is instrumental in establishing the proton gradient required for ATP synthesis in this phase. Subsequently, the light-independent reactions, also known as the Calvin cycle, utilize the ATP and NADPH generated in the light-dependent reactions to fix carbon dioxide and synthesize sugars.

The Electron Transport Chain at the Cellular Level

Within the electron transport chain (ETC), electrons embark on a journey through a sequence of protein complexes, each exhibiting an increasing reduction potential. This stepwise electron transfer releases energy at each step. A significant portion of this energy is dissipated as heat, but a substantial amount is harnessed to actively pump hydrogen ions (H+) from the mitochondrial matrix into the intermembrane space, thereby creating a proton gradient. This proton gradient manifests as an increased acidity in the intermembrane space and an electrical potential difference, with a positive charge on the outside and a negative charge on the inside of the inner mitochondrial membrane. The key protein complexes of the ETC, arranged in functional order, are Complex I, Complex II, Coenzyme Q, Complex III, Cytochrome C, and Complex IV.

  • Complex II, also known as succinate dehydrogenase, serves as an alternative entry point for electrons into the ETC. It accepts electrons from succinate, an intermediate in the citric acid cycle. When succinate undergoes oxidation to fumarate, two electrons are captured by FAD within Complex II. FAD subsequently transfers these electrons to Fe-S clusters and then to coenzyme Q, mirroring the electron transfer pathway in Complex I. However, a critical distinction is that Complex II does not translocate protons across the membrane. Consequently, the pathway involving Complex II yields less ATP compared to the pathway initiated by Complex I.[5],[6]

    • Reaction: Succinate + FAD → Fumarate + 2 H+(matrix) + FADH2
    • Reaction: FADH2 + CoQ → FAD + CoQH2

  • Coenzyme Q, also known as ubiquinone (CoQ), is a mobile electron carrier composed of a quinone group and a hydrophobic tail. Its primary role is to ferry electrons from Complexes I and II to Complex III. Coenzyme Q undergoes reduction through the Q cycle, transitioning through semiquinone (partially reduced, radical form CoQH–) and ubiquinol (fully reduced CoQH2) states. The intricate details of the Q cycle are further elaborated under Complex III.

ATP synthase, also designated as Complex V, is the molecular machine that harnesses the proton gradient generated by the ETC to synthesize ATP. ATP synthase is composed of two principal subunits, F0 and F1, functioning as a rotary motor system. The F0 subunit is hydrophobic and deeply embedded within the inner mitochondrial membrane. It features a proton channel that undergoes repeated protonation and deprotonation as H+ ions flow down their electrochemical gradient from the intermembrane space back into the matrix. This cyclical ionization of F0 induces rotation, which in turn alters the conformation of the F1 subunits. The F1 subunit is hydrophilic and protrudes into the mitochondrial matrix. Conformational changes within the F1 subunits catalyze the phosphorylation of ADP by inorganic phosphate (Pi), resulting in ATP formation. The stoichiometry of ATP synthesis is such that approximately 1 ATP molecule is generated for every 4 H+ ions that traverse ATP synthase. Intriguingly, ATP synthase can also operate in reverse, consuming ATP to pump protons against their gradient, a phenomenon observed in certain bacteria.[15],[16],[17]

Delving into the Molecular Level of the Electron Transport Chain

Nicotinamide adenine dinucleotide exists in two interconvertible forms: NAD+ (oxidized) and NADH (reduced). It is a dinucleotide, composed of two nucleosides linked by phosphate groups. One nucleoside contains an adenine base, while the other features nicotinamide. In metabolic redox reactions, NAD+ acts as an electron acceptor, as depicted in Reaction 1.

  • Reaction 1: RH2 + NAD+ → R + H+ + NADH

Where RH2 represents a reduced reactant, such as a sugar molecule.

NADH, carrying high-energy electrons, enters the ETC at Complex I. As electrons are transferred through the ETC from NADH to the final electron acceptor, oxygen, a total of 10 H+ ions are pumped across the inner mitochondrial membrane (4 from Complex I, 4 from Complex III, and 2 from Complex IV). Given that ATP synthase synthesizes approximately 1 ATP for every 4 H+ ions, the oxidation of 1 NADH molecule theoretically yields about 2.5 ATP molecules (some sources round this value to 3 ATP). When NADH is oxidized, it releases its electrons, regenerating NAD+, as shown in Reaction 2.

  • Reaction 2: NADH → H+ + NAD+ + 2 e–

Flavin adenine dinucleotide (FAD) also participates as a crucial electron carrier in the ETC. FAD exists in four redox states, with the three primary forms being FAD (quinone, fully oxidized form), FADH– (semiquinone, partially oxidized), and FADH2 (hydroquinone, fully reduced). FAD is structurally similar to NAD+, consisting of an adenine nucleotide linked to a flavin mononucleotide (FMN) via phosphate groups. FMN is derived, in part, from vitamin B2 (riboflavin). A key difference is that FAD in its oxidized form contains a highly stable aromatic ring, while FADH2 does not. The oxidation of FADH2 to FAD results in the restoration of the aromatic ring and the release of energy, as illustrated in Reaction 3. This characteristic renders FAD a potent oxidizing agent, exhibiting an even more positive reduction potential than NAD+. FADH2 feeds electrons into the ETC at Complex II and its oxidation contributes to the pumping of a total of 6 H+ ions (4 from Complex III and 2 from Complex IV). Consequently, the oxidation of 1 FADH2 molecule yields approximately 1.5 ATP molecules (some sources round this to 2 ATP).[18]

  • Reaction 3: FADH2 → FAD + 2 H+ + 2 e–

Beyond its role in the ETC, FAD also participates in various other metabolic pathways, including DNA repair (MTHF repair of UV damage), fatty acid beta-oxidation (acyl-CoA dehydrogenase), and the synthesis of essential coenzymes (CoA, CoQ, heme).

Clinical Significance of the Electron Transport Chain

The electron transport chain’s crucial role in energy production makes it a target for various pharmacological and toxicological agents. Disruptions to the ETC can have severe clinical consequences.

Uncoupling Agents

Uncoupling agents are compounds that disrupt the tight coupling between the electron transport chain and ATP synthesis by ATP synthase. These agents effectively dissociate the proton gradient from ATP production, preventing efficient ATP formation. Many uncoupling agents act by disrupting the phospholipid bilayer of mitochondrial membranes, increasing their permeability to protons. This proton leak diminishes the electrochemical gradient, as protons flow back into the mitochondrial matrix without passing through ATP synthase. Consequently, the energy of the proton gradient is dissipated as heat rather than being harnessed for ATP synthesis.

Cells treated with uncoupling agents experience ATP depletion. To compensate, the ETC becomes hyperactive, attempting to restore the proton gradient and drive ATP synthesis. However, this futile cycle of electron transport and proton pumping leads to increased heat production. The body temperature rises as a result of this metabolic overdrive. Furthermore, the cellular energy deficit may trigger a metabolic shift towards anaerobic fermentation, potentially leading to type B lactic acidosis in affected individuals.[19]

Examples of Uncoupling Agents:

  • Aspirin (Salicylic Acid): At high doses, aspirin can act as an uncoupling agent.
  • Thermogenin: This protein, naturally found in brown adipose tissue, is a physiological uncoupling agent, responsible for heat generation in newborns and hibernating animals.

Oxidative Phosphorylation Inhibitors

A range of toxins and pharmacological agents can directly inhibit specific components of the electron transport chain or ATP synthase, effectively blocking oxidative phosphorylation. These inhibitors can have profound cellular and systemic effects.

Examples of Oxidative Phosphorylation Inhibitors:

  • Rotenone (and some barbiturates): Inhibits Complex I by binding to the coenzyme Q binding site.
  • Carboxin: Inhibits Complex II, also by interfering with the coenzyme Q binding site.
    • Note: Carboxin, a fungicide, is largely obsolete due to the availability of broader-spectrum alternatives. Like rotenone, it targets the ubiquinone binding site on Complex II.
  • Doxorubicin: This chemotherapeutic drug is theorized to interfere with coenzyme Q function.
  • Antimycin A: Inhibits Complex III (cytochrome c reductase) by binding at the Qi binding site.
    • Note: Antimycin A, a piscicide, prevents ubiquinone binding and electron acceptance, thus disrupting the Q cycle and the recycling of ubiquinol (CoQH2).
  • Carbon Monoxide (CO): Inhibits Complex IV (cytochrome c oxidase).
  • Cyanide (CN): Inhibits Complex IV (cytochrome c oxidase).
    • Note: Cyanide also binds to and inhibits cytochrome c oxidase (Complex IV). Cyanide poisoning and carbon monoxide poisoning can present with similar symptoms of tissue hypoxia. However, cyanide poisoning often manifests with hypoxia unresponsive to supplemental oxygen and a characteristic almond odor on the breath. Common sources of cyanide exposure include smoke inhalation from house fires (combustion of furniture or rugs), jewelry cleaning solutions, plastic or rubber manufacturing, iatrogenic sources (nitroprusside administration), and even certain fruit seeds (apricots, peaches, apples).
    • Treatment for Cyanide Poisoning: Treatment strategies include administering nitrites to oxidize hemoglobin iron from Fe2+ to Fe3+, forming methemoglobin. Methemoglobin binds cyanide, preventing it from interacting with the ETC. However, methemoglobin reduces oxygen-carrying capacity, necessitating further treatment with methylene blue to reduce Fe3+ back to Fe2+. Alternative treatments include hydroxocobalamin (a form of vitamin B12) or thiosulfate, although thiosulfate is often used in combination therapy with nitrites due to its slower onset of action.[32]
  • Oligomycin: Inhibits ATP synthase (Complex V).

Review of the Electron Transport Chain

Figure

Diagram illustrating the electron transport chain within the inner mitochondrial membrane, highlighting protein complexes I-IV, coenzyme Q, cytochrome c, ATP synthase, and the proton gradient driving ATP synthesis. Illustration by Emma Gregory

References

  1. Lencina AM, Franza T, Sullivan MJ, Ulett GC, Ipe DS, Gaudu P, Gennis RB, Schurig-Briccio LA. Type 2 NADH Dehydrogenase Is the Only Point of Entry for Electrons into the Streptococcus agalactiae Respiratory Chain and Is a Potential Drug Target. mBio. 2018 Jul 03;9(4) [PMC free article: PMC6030563] [PubMed: 29970468]
  2. Hirst J. Towards the molecular mechanism of respiratory complex I. Biochem J. 2009 Dec 23;425(2):327-39. [PubMed: 20025615]
  3. Sazanov LA, Hinchliffe P. Structure of the hydrophilic domain of respiratory complex I from Thermus thermophilus. Science. 2006 Mar 10;311(5766):1430-6. [PubMed: 16469879]
  4. Hirst J. Energy transduction by respiratory complex I–an evaluation of current knowledge. Biochem Soc Trans. 2005 Jun;33(Pt 3):525-9. [PubMed: 15916556]
  5. Yankovskaya V, Horsefield R, Törnroth S, Luna-Chavez C, Miyoshi H, Léger C, Byrne B, Cecchini G, Iwata S. Architecture of succinate dehydrogenase and reactive oxygen species generation. Science. 2003 Jan 31;299(5607):700-4. [PubMed: 12560550]
  6. Horsefield R, Iwata S, Byrne B. Complex II from a structural perspective. Curr Protein Pept Sci. 2004 Apr;5(2):107-18. [PubMed: 15078221]
  7. Geertman JM, van Maris AJ, van Dijken JP, Pronk JT. Physiological and genetic engineering of cytosolic redox metabolism in Saccharomyces cerevisiae for improved glycerol production. Metab Eng. 2006 Nov;8(6):532-42. [PubMed: 16891140]
  8. Thorpe C, Kim JJ. Structure and mechanism of action of the acyl-CoA dehydrogenases. FASEB J. 1995 Jun;9(9):718-25. [PubMed: 7601336]
  9. Sun C, Benlekbir S, Venkatakrishnan P, Wang Y, Hong S, Hosler J, Tajkhorshid E, Rubinstein JL, Gennis RB. Structure of the alternative complex III in a supercomplex with cytochrome oxidase. Nature. 2018 May;557(7703):123-126. [PMC free article: PMC6004266] [PubMed: 29695868]
  10. Iwata S, Lee JW, Okada K, Lee JK, Iwata M, Rasmussen B, Link TA, Ramaswamy S, Jap BK. Complete structure of the 11-subunit bovine mitochondrial cytochrome bc1 complex. Science. 1998 Jul 03;281(5373):64-71. [PubMed: 9651245]
  11. Trumpower BL. The protonmotive Q cycle. Energy transduction by coupling of proton translocation to electron transfer by the cytochrome bc1 complex. J Biol Chem. 1990 Jul 15;265(20):11409-12. [PubMed: 2164001]
  12. Hunte C, Palsdottir H, Trumpower BL. Protonmotive pathways and mechanisms in the cytochrome bc1 complex. FEBS Lett. 2003 Jun 12;545(1):39-46. [PubMed: 12788490]
  13. Calhoun MW, Thomas JW, Gennis RB. The cytochrome oxidase superfamily of redox-driven proton pumps. Trends Biochem Sci. 1994 Aug;19(8):325-30. [PubMed: 7940677]
  14. Schmidt-Rohr K. Oxygen Is the High-Energy Molecule Powering Complex Multicellular Life: Fundamental Corrections to Traditional Bioenergetics. ACS Omega. 2020 Feb 11;5(5):2221-2233. [PMC free article: PMC7016920] [PubMed: 32064383]
  15. Lovero D, Giordano L, Marsano RM, Sanchez-Martinez A, Boukhatmi H, Drechsler M, Oliva M, Whitworth AJ, Porcelli D, Caggese C. Characterization of Drosophila ATPsynC mutants as a new model of mitochondrial ATP synthase disorders. PLoS One. 2018;13(8):e0201811. [PMC free article: PMC6086398] [PubMed: 30096161]
  16. Okuno D, Iino R, Noji H. Rotation and structure of FoF1-ATP synthase. J Biochem. 2011 Jun;149(6):655-64. [PubMed: 21524994]
  17. Junge W, Nelson N. ATP synthase. Annu Rev Biochem. 2015;84:631-57. [PubMed: 25839341]
  18. Hinkle PC. P/O ratios of mitochondrial oxidative phosphorylation. Biochim Biophys Acta. 2005 Jan 07;1706(1-2):1-11. [PubMed: 15620362]
  19. Barrett MA, Zheng S, Roshankar G, Alsop RJ, Belanger RK, Huynh C, Kučerka N, Rheinstädter MC. Interaction of aspirin (acetylsalicylic acid) with lipid membranes. PLoS One. 2012;7(4):e34357. [PMC free article: PMC3328472] [PubMed: 22529913]
  20. Warrick BJ, King A, Smolinske S, Thomas R, Aaron C. A 29-year analysis of acute peak salicylate concentrations in fatalities reported to United States poison centers. Clin Toxicol (Phila). 2018 Sep;56(9):846-851. [PubMed: 29431532]
  21. Cinti S. The adipose organ. Prostaglandins Leukot Essent Fatty Acids. 2005 Jul;73(1):9-15. [PubMed: 15936182]
  22. Enerbäck S. The origins of brown adipose tissue. N Engl J Med. 2009 May 07;360(19):2021-3. [PubMed: 19420373]
  23. Zhou W, Faraldo-Gómez JD. Membrane plasticity facilitates recognition of the inhibitor oligomycin by the mitochondrial ATP synthase rotor. Biochim Biophys Acta Bioenerg. 2018 Sep;1859(9):789-796. [PMC free article: PMC6176861] [PubMed: 29630891]
  24. Kamalian L, Douglas O, Jolly CE, Snoeys J, Simic D, Monshouwer M, Williams DP, Kevin Park B, Chadwick AE. The utility of HepaRG cells for bioenergetic investigation and detection of drug-induced mitochondrial toxicity. Toxicol In Vitro. 2018 Dec;53:136-147. [PubMed: 30096366]
  25. Wood DM, Alsahaf H, Streete P, Dargan PI, Jones AL. Fatality after deliberate ingestion of the pesticide rotenone: a case report. Crit Care. 2005 Jun;9(3):R280-4. [PMC free article: PMC1175899] [PubMed: 15987402]
  26. Lupescu A, Jilani K, Zbidah M, Lang F. Induction of apoptotic erythrocyte death by rotenone. Toxicology. 2012 Oct 28;300(3):132-7. [PubMed: 22727881]
  27. Wallace KB. Doxorubicin-induced cardiac mitochondrionopathy. Pharmacol Toxicol. 2003 Sep;93(3):105-15. [PubMed: 12969434]
  28. Weaver LK. Clinical practice. Carbon monoxide poisoning. N Engl J Med. 2009 Mar 19;360(12):1217-25. [PubMed: 19297574]
  29. Sato K, Tamaki K, Hattori H, Moore CM, Tsutsumi H, Okajima H, Katsumata Y. Determination of total hemoglobin in forensic blood samples with special reference to carboxyhemoglobin analysis. Forensic Sci Int. 1990 Nov;48(1):89-96. [PubMed: 2279722]
  30. Barker SJ, Tremper KK. The effect of carbon monoxide inhalation on pulse oximetry and transcutaneous PO2. Anesthesiology. 1987 May;66(5):677-9. [PubMed: 3578881]
  31. Raub JA, Mathieu-Nolf M, Hampson NB, Thom SR. Carbon monoxide poisoning–a public health perspective. Toxicology. 2000 Apr 07;145(1):1-14. [PubMed: 10771127]
  32. Jensen P, Wilson MT, Aasa R, Malmström BG. Cyanide inhibition of cytochrome c oxidase. A rapid-freeze e.p.r. investigation. Biochem J. 1984 Dec 15;224(3):829-37. [PMC free article: PMC1144519] [PubMed: 6098268]
  33. Shchepina LA, Pletjushkina OY, Avetisyan AV, Bakeeva LE, Fetisova EK, Izyumov DS, Saprunova VB, Vyssokikh MY, Chernyak BV, Skulachev VP. Oligomycin, inhibitor of the F0 part of H+-ATP-synthase, suppresses the TNF-induced apoptosis. Oncogene. 2002 Nov 21;21(53):8149-57. [PubMed: 12444550]

Disclosure: Maria Ahmad declares no relevant financial relationships with ineligible companies.

Disclosure: Adam Wolberg declares no relevant financial relationships with ineligible companies.

Disclosure: Chadi Kahwaji declares no relevant financial relationships with ineligible companies.

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