The electron transport chain is a series of four protein complexes that couple redox reactions, creating an electrochemical gradient that leads to the creation of ATP in a complete system named oxidative phosphorylation. It occurs in mitochondria in both cellular respiration and photosynthesis. In the former, the electrons come from breaking down organic molecules, and energy is released. In the latter, the electrons enter the chain after being excited by light, and the energy released is used to build carbohydrates.
Aerobic cellular respiration is made up of three parts: glycolysis, the citric acid (Krebs) cycle, and oxidative phosphorylation. In glycolysis, glucose metabolizes into two molecules of pyruvate, with an output of ATP and nicotinamide adenine dinucleotide (NADH). Each pyruvate oxidizes into acetyl CoA and an additional molecule of NADH and carbon dioxide (CO2). The acetyl CoA is then used in the citric acid cycle, which is a chain of chemical reactions that produce CO2, NADH, flavin adenine dinucleotide (FADH2), and ATP. In the final step, the three NADH and one FADH2 amassed from the previous steps are used in oxidative phosphorylation, to make water and ATP.
Oxidative phosphorylation has two parts: the electron transport chain (ETC) and chemiosmosis. The ETC is a collection of proteins bound to the inner mitochondrial membrane and organic molecules, which electrons pass through in a series of redox reactions, and release energy. The energy released forms a proton gradient, which is used in chemiosmosis to make a large amount of ATP by the protein ATP-synthase.
Photosynthesis is a metabolic process that converts light energy into chemical energy to build sugars. In the light-dependent reactions, light energy and water are used to make ATP, NADPH, and oxygen (O2). The proton gradient used to make the ATP forms via an electron transport chain. In the light-independent reactions, sugar is made from the ATP and NADPH from the previous reactions.
In the electron transport chain (ETC), the electrons go through a chain of proteins that increases its reduction potential and causes a release in energy. Most of this energy is dissipated as heat or utilized to pump hydrogen ions (H+) from the mitochondrial matrix to the intermembrane space and create a proton gradient. This gradient increases the acidity in the intermembrane space and creates an electrical difference with a positive charge outside and a negative charge inside. The ETC proteins in a general order are complex I, complex II, coenzyme Q, complex III, cytochrome C, and complex IV.
ATP synthase, also called complex V, uses the ETC generated proton gradient across the inner mitochondrial membrane to form ATP. ATP-synthase contains up of F0 and F1 subunits, which act as a rotational motor system. F0 is hydrophobic and embedded in the inner mitochondrial membrane. It contains a proton corridor that is protonated and deprotonated repeatedly as H+ ions flow down the gradient from intermembrane space to matrix. The alternating ionization of F0 causes rotation, which alters the orientation of the F1 subunits. F1 is hydrophilic and faces the mitochondrial matrix. Conformational changes in F1 subunits catalyze the formation of ATP from ADP and Pi. For every 4 H+ ions, 1 ATP is produced. ATP-synthase can also be forced to run in reverse, consuming ATP to produce a hydrogen gradient, as is seen in some bacteria.
Nicotinamide adenine dinucleotide has two forms: NAD+ (oxidized) and NADH (reduced). It is a dinucleotide connected by phosphate groups. One nucleoside has an adenine base and the other nicotinamide. When involved in metabolic redox reactions, the mechanism is as shown in Reaction 1.
R is the reactant, for example, sugar.
NADH enters the ETC at complex I and produces a total of 10 H+ ions through the ETC (4 from complex I, 4 from complex III, and 2 from complex IV). ATP-synthase synthesizes 1 ATP for 4 H+ ions. Therefore, 1 NADH = 10 H+, and 10/4 H+ per ATP = 2.5 ATP per NADH (**some sources round up**). When NADH is oxidized, it breaks into NAD+, H+, and 2 e- as shown in Reaction 2.
Flavin adenine dinucleotide has 4 redox states, 3 of them being FAD (quinone, fully oxidized form), FADH- (semiquinone, partially oxidized), and FADH2 (hydroquinone, fully reduced). FAD is made up of an adenine nucleotide and a flavin mononucleotide (FMN), connected by phosphate groups. FMN is synthesized in part from vitamin B2 (riboflavin). FAD contains a highly stable aromatic ring, and FADH2 does not. When FADH2 oxidizes, it becomes aromatic and releases energy, as seen in Reaction 3. This state makes FAD a potent oxidizing agent, with an even more positive reduction potential than NAD. FADH2 enters the ETC at complex II and creates a total of 1.5 ATP (4 H+ from complex III, and 2 H+ from complex IV; 6/4 H+ per ATP = 1.5 ATP per FADH2 **some sources round up**).
FAD also functions in several metabolic pathways outside of the ETC, including DNA repair (MTHF repair of UV damage), fatty acid beta-oxidation (acyl-CoA dehydrogenase), and synthesis of coenzymes (CoA, CoQ, heme).
An uncoupling agent dissociates the electron transport chain from phosphorylation by ATP-synthase, preventing the formation of ATP. Disruption of the phospholipid bilayer of membranes causes a fluid-like and disorganized state, which allows protons to flow through more freely. This proton leak weakens the electrochemical gradient, while also transferring protons without the use of ATP-synthase such that no ATP is produced.
While the cell becomes starved of ATP, the ETC will overwork in an attempt to shuttle more and more electrons to ATP-synthase without success. The ETC regularly produces heat as the electrons transfer from one carrier to the next, and this overactivity will raise the body temperature as a result. Additionally, cells will adapt to utilizing fermentation as if in anaerobic conditions; this may cause a type B lactic acidosis in affected patients.
Aspirin (Salicylic Acid)
Oxidative Phosphorylation Inhibitors
Certain poisons can inhibit cellular oxidative phosphorylation such as rotenone, carboxin, antimycin A, cyanide, carbon monoxide (CO), sodium azide, and oligomycin. Rotenone inhibits complex I, carboxin inhibits complex II, antimycin A inhibits complex III, and cyanide and CO inhibit complex IV. Oligomycin inhibits ATP synthase.
Rotenone (and some barbiturates) – inhibits complex I (coenzyme Q binding site)
Carboxin – inhibits complex II (coenzyme Q binding site)
Doxorubicin – coenzyme Q (theoretical)
Antimycin A – inhibits complex III (cytochrome c reductase)
Carbon Monoxide (CO) – inhibits complex IV (cytochrome c oxidase)
Cyanide (CN) – inhibits complex IV (cytochrome c oxidase)
Oligomycin – inhibits ATP-synthase (complex V)
|||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 3 [PubMed PMID: 29970468]|
|||Hirst J, Towards the molecular mechanism of respiratory complex I. The Biochemical journal. 2009 Dec 23; [PubMed PMID: 20025615]|
|||Sazanov LA,Hinchliffe P, Structure of the hydrophilic domain of respiratory complex I from Thermus thermophilus. Science (New York, N.Y.). 2006 Mar 10; [PubMed PMID: 16469879]|
|||Hirst J, Energy transduction by respiratory complex I--an evaluation of current knowledge. Biochemical Society transactions. 2005 Jun; [PubMed PMID: 15916556]|
|||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 (New York, N.Y.). 2003 Jan 31; [PubMed PMID: 12560550]|
|||Horsefield R,Iwata S,Byrne B, Complex II from a structural perspective. Current protein [PubMed PMID: 15078221]|
|||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. Metabolic engineering. 2006 Nov; [PubMed PMID: 16891140]|
|||Thorpe C,Kim JJ, Structure and mechanism of action of the acyl-CoA dehydrogenases. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 1995 Jun; [PubMed PMID: 7601336]|
|||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 [PubMed PMID: 29695868]|
|||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 (New York, N.Y.). 1998 Jul 3; [PubMed PMID: 9651245]|
|||Trumpower BL, The protonmotive Q cycle. Energy transduction by coupling of proton translocation to electron transfer by the cytochrome bc1 complex. The Journal of biological chemistry. 1990 Jul 15; [PubMed PMID: 2164001]|
|||Hunte C,Palsdottir H,Trumpower BL, Protonmotive pathways and mechanisms in the cytochrome bc1 complex. FEBS letters. 2003 Jun 12; [PubMed PMID: 12788490]|
|||Calhoun MW,Thomas JW,Gennis RB, The cytochrome oxidase superfamily of redox-driven proton pumps. Trends in biochemical sciences. 1994 Aug; [PubMed PMID: 7940677]|
|||Schmidt-Rohr K, Oxygen Is the High-Energy Molecule Powering Complex Multicellular Life: Fundamental Corrections to Traditional Bioenergetics. ACS omega. 2020 Feb 11; [PubMed PMID: 32064383]|
|||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 [PubMed PMID: 30096161]|
|||Okuno D,Iino R,Noji H, Rotation and structure of FoF1-ATP synthase. Journal of biochemistry. 2011 Jun; [PubMed PMID: 21524994]|
|||Junge W,Nelson N, ATP synthase. Annual review of biochemistry. 2015; [PubMed PMID: 25839341]|
|||Hinkle PC, P/O ratios of mitochondrial oxidative phosphorylation. Biochimica et biophysica acta. 2005 Jan 7; [PubMed PMID: 15620362]|
|||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; [PubMed PMID: 22529913]|
|||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. Clinical toxicology (Philadelphia, Pa.). 2018 Sep [PubMed PMID: 29431532]|
|||Cinti S, The adipose organ. Prostaglandins, leukotrienes, and essential fatty acids. 2005 Jul; [PubMed PMID: 15936182]|
|||Enerbäck S, The origins of brown adipose tissue. The New England journal of medicine. 2009 May 7; [PubMed PMID: 19420373]|
|||Zhou W,Faraldo-Gómez JD, Membrane plasticity facilitates recognition of the inhibitor oligomycin by the mitochondrial ATP synthase rotor. Biochimica et biophysica acta. 2018 Sep [PubMed PMID: 29630891]|
|||Kamalian L,Douglas O,Jolly C,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. Toxicology in vitro : an international journal published in association with BIBRA. 2018 Aug 7 [PubMed PMID: 30096366]|
|||Wood DM,Alsahaf H,Streete P,Dargan PI,Jones AL, Fatality after deliberate ingestion of the pesticide rotenone: a case report. Critical care (London, England). 2005 Jun; [PubMed PMID: 15987402]|
|||Lupescu A,Jilani K,Zbidah M,Lang F, Induction of apoptotic erythrocyte death by rotenone. Toxicology. 2012 Oct 28; [PubMed PMID: 22727881]|
|||Wallace KB, Doxorubicin-induced cardiac mitochondrionopathy. Pharmacology [PubMed PMID: 12969434]|
|||Weaver LK, Clinical practice. Carbon monoxide poisoning. The New England journal of medicine. 2009 Mar 19; [PubMed PMID: 19297574]|
|||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 science international. 1990 Nov; [PubMed PMID: 2279722]|
|||Barker SJ,Tremper KK, The effect of carbon monoxide inhalation on pulse oximetry and transcutaneous PO2. Anesthesiology. 1987 May; [PubMed PMID: 3578881]|
|||Raub JA,Mathieu-Nolf M,Hampson NB,Thom SR, Carbon monoxide poisoning--a public health perspective. Toxicology. 2000 Apr 7; [PubMed PMID: 10771127]|
|||Jensen P,Wilson MT,Aasa R,Malmström BG, Cyanide inhibition of cytochrome c oxidase. A rapid-freeze e.p.r. investigation. The Biochemical journal. 1984 Dec 15; [PubMed PMID: 6098268]|
|||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; [PubMed PMID: 12444550]|