Scientific Online Resource System

Biomedical Reviews

Debunking Chemiosmosis and Proposing Murburn Concept as the Operative Principle for Cellular Respiration

Kelath Murali Manoj


During cellular respiration, aerobic eukaryotes employ molecular oxygen within the mitochondria, to generate the energy currency of ATP. Chemiosmosis, the long-standing mechanism of mitochondrial oxidative redox metabolism, vouches for the `harnessing of a trans-membrane proton potential` for the synthesis of ATP. Herein, select elements of the chemiosmosis proposal are critically reviewed and debunked. Further, based on simple analogies and structurefunction correlations, murburn concept (connoting to "mured burning` or mild unrestricted burning), the recently established mechanism for microsomal xenobiotic metabolism, is advocated as a probable molecular explanation for mitochondrial oxidative phosphorylation. It is envisaged that the stochastic mechanism of murburn concept could play pivotal roles in several biological redox schemes. The concept necessitates a paradigm shift in mitochondrial biochemistry. Biomed Rev 2017; 28: 31-48.

Keywords: murburn concept, cellular respiration, mitochondrial oxidative phosphorylation, microsomal xenobiotic metabolism, ATP synthesis, chemiosmosis, reactive oxygen species

Full Text


Nicholls DG, Ferguson SJ. Bioenergetics 2. London: Academic Press, 1992.

Slater EC. Mechanism of phosphorylation in the respiratory chain. Nature 1953;172:975-978.

Mitchell P. Coupling of phosphorylation to electron and hydrogen transfer by a chemi-osmotic type of mechanism. Nature 1961;191:144-148.

Boyer PD. Phosphohistidine. Science 1963;141:1147-1153. DOI:10.1126/science.141.3586.1147.

Jagendorf AT, Uribe E. ATP formation caused by acidbase transition of spinach chloroplasts. Proc Natl Acad Sci USA 1966;55:170-177.

Reid R, Moyle J, Mitchell P. Synthesis of adenosine triphosphate by a protonmotive force in rat liver mitochondria. Nature 1966;212:257-258.

Liberman E, Topaly V, Tsofina L. Mechanism of coupling of oxidative phosphorylation and the membrane potential of mitochondria. Nature 1969;222:1076-1078.

Racker E, Stoeckenius W. Reconstitution of purple membrane vesicles catalyzing light-driven proton uptake and adenosine triphosphate formation. J Biol Chem 1974;249:662-663.

Brand MD, Lehninger AL. H+/ATP ratio during ATP hydrolysis by mitochondria: modification of the chemiosmotic theory. Proc Natl Acad Sci USA 1977;74:1955-1959.

Borst P. Edward Charles Slater. 16 January 1917 - 26 March 2016. Biographical Memoirs of Fellows of the Royal Society. 2017. DOI: 10.1098/rsbm.2016.0024

Slater E. An evaluation of the Mitchell hypothesis of chemiosmotic coupling in oxidative and photosynthetic phosphorylation. Eur J Biochem 1967;1:317-326. DOI: 10.1111/j.1432-1033.1967.tb00076.x

Slater E. The mechanism of the conservation of energy of biological oxidations. FEBS J 1987;166:489-504. DOI: 10.1111/j.1432-1033.1987.tb13542.x

Ling GN. Oxidative phosphorylation and mitochondrial physiology: a critical review of chemiosmotic theory, and reinterpretation by the association-induction hypothesis. Physiol Chem Phys 1981;13:29-96.

Wainio W. An assessment of the chemiosmotic hypothesis of mitochondrial energy transduction. Int Rev Cytol 1985;96:29-50. DOI: 10.1016/S0074-7696(08)60593-8

Montellano PRO. Cytochrome P450: Structure, Mechanism, and Biochemistry. 3rd edition. New York, Kluwer, Academic Plenum Publishers, 2005.

Lehninger AL, Nelson DL, Cox M. Principles of Biochemistry. Palgrave Macmillan Ltd, 2004.

Berg JM, Tymoczko JL, Stryer L. Biochemistry, 5th edition. 2002.

Voet D, Voet JG. Biochemistry, 4th edition. Wiley, Hoboken, NJ, USA, 2011.

Gupte S, Wu E-S, Hoechli L, Hoechli M, Jacobson K, Sowers AE, et al. Relationship between lateral diffusion, collision frequency, and electron transfer of mitochondrial inner membrane oxidation-reduction components. Proc Natl Acad Sci U S A. 1984;81(9):2606-2610.

Schwerzmann K, Cruz-Orive LM, Eggman R, Sänger A, Weibel ER. Molecular architecture of the inner membrane of mitochondria from rat liver: a combined biochemical and stereological study. J Cell Biol 1986;102:97-103. DOI: 10.1083/jcb.102.1.97

Biegel CM, Gould JM. Kinetics of hydrogen ion diffusion across phospholipid vesicle membranes. Biochemistry 1981;20:3474-3479. DOI: 10.1021/bi00515a026

Nicholls DG. Mitochondrial membrane potential and aging. Aging Cell 2004;3:35-40. DOI: 10.1111/j.1474-9728.2003.00079.x

Nath S. Beyond the chemiosmotic theory: Analysis of key fundamental aspects of energy coupling in oxidative phosphorylation in the light of a torsional mechanism of energy transduction and ATP synthesis - Invited review Part 1. J Bioenerg Biomemb 2010;42:293-300.

Nath S. Beyond the chemiosmotic theory: Analysis of key fundamental aspects of energy coupling in oxidative phosphorylation in the light of a torsional mechanism of energy transduction and ATP synthesis - Invited review part 2. J Bioenerg Biomemb 2010;42:301-309. DOI: 10.1007/s10863-010-9296-5

Cross R, Taggart JV, Covo G, Green D. Studies on the cyclophorase system VI. The coupling of oxidation and phosphorylation. J Biol Chem 1949;177:655-678.

Copenhaver J, Lardy HA. Oxidative phosphorylations: Pathways and yield in mitochondrial preparations. J Biol Chem 1952;195:225-238.

Chance B, Williams G. Respiratory enzymes in oxidative phosphorylation I. Kinetics of oxygen utilization. J Biol Chem 1955;217:383-394.

Lemasters J. The ATP-to-oxygen stoichiometries of oxidative phosphorylation by rat liver mitochondria. An analysis of ADP-induced oxygen jumps by linear nonequilibrium thermodynamics. J Biol Chem 1984;259:13123-13130.

Beavis AD, Lehninger AL. The upper and lower limits of the mechanistic stoichiometry of mitochondrial oxidative phosphorylation. FEBS J 1986;158:315-322. DOI: 10.1111/j.1432-1033.1986.tb09753.x

Stoner CD. Determination of the P/2e-stoichiometries at the individual coupling sites in mitochondrial oxidative phosphorylation. Evidence for maximum values of 1.0, 0.5, and 1.0 at sites 1, 2, and 3. J Biol Chem 1987;262:10445-10453.

Toth PP, Sumerix KJ, Ferguson-Miller S, Suelter CH. Respiratory control and ADP: O coupling ractions of isolated chick heart mitochondria. Arch Biochem Biophys 1990;276:199-211.

Lee C, Gu Q, Xiong Y, Mitchell R, Ernster L. P/O ratios reassessed: mitochondrial P/O ratios consistently exceed 1.5 with succinate and 2.5 with NAD-linked substrates. FASEB J 1996;10:345-350. DOI: 10.1016/j.bbabio.2004.09.004

Watt IN, Montgomery MG, Runswick MJ, Leslie AG, Walker JE. Bioenergetic cost of making an adenosine triphosphate molecule in animal mitochondria. Proc Nat Acad Sci USA 2010;107:16823-16827. DOI: 10.1073/pnas.1011099107

Chance B, Williams G. The respiratory chain and oxidative phosphorylation. Adv Enzymol Relat Areas Mol Biol 1956;17:65-134. DOI: 10.1002/9780470122624.ch2

Estabrook RW: Mitochondrial respiratory control and the polarographic measurement of ADP: O ratios. In: Estabrook RE, Pullman MF (Eds), Methods in Enzymology. Volume 10. New York: Academic Press, 1967; pp 41-47.

Manoj KM, Parashar A, Gade SK, Venkatachalam A. Functioning of microsomal cytochrome P450s: Murburn concept explains the metabolism of xenobiotics in hepatocytes. Front Pharmacol 2016;7:161. DOI: 10.3389/fphar.2016.00161

Szewczyk A, Wojtczak L. Mitochondria as a pharmacological target. Pharmacolo Rev 2002;54:101-127.

Parikh S, Saneto R, Falk MJ, Anselm I, Cohen BH, Haas R. A modern approach to the treatment of mitochondrial disease. Curr Treat Options Neurol 2009;11:414-430.

Scatena R. Mitochondria and drugs. Adv Exp Med Biol 2012;942:329-346.

Picard M, Wallace DC, Burelle Y. The rise of mitochondria in medicine. Mitochondrion. 2016;30(105-116. doi: 10.1016/j.mito.2016.07.003

Wheaton WW, Weinberg SE, Hamanaka RB, Soberanes S, Sullivan LB, Anso E, Glasauer A, et al. Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis. eLife. 2014;3(e02242. doi: 10.7554/eLife.02242.001

Gohil VM, Sheth SA, Nilsson R, Wojtovich AP, Lee JH, Perocchi F, Chen W, et al. Nutrient-sensitized screening for drugs that shift energy metabolism from mitochondrial respiration to glycolysis. Nat Biotechnol 2010;28:249-255. DOI: 10.1038/nbt.1606

Venkatachalam A, Parashar A, Manoj KM. Functioning of drug-metabolizing microsomal cytochrome P450s. 1. In silico probing of proteins suggest that the distal heme `active site` pocket plays a relatively `passive role` in some enzyme-substrate interactions. In Silico Pharmacol 2016;4:1. DOI: 10.1186/s40203-016-0016-7

Bhagwat SV, Mullick J, Raza H, Avadhani NG. Constitutive and inducible cytochromes P450 in rat lung mitochondria: xenobiotic induction, relative abundance, and catalytic properties. Toxicol Appl Pharmacol 1999;156:231-240. DOI: 10.1006/taap.1999.8646

Robin M-A, Anandatheerthavarada HK, Fang J-K, Cudic M, Otvos L, Avadhani NG. Mitochondrial targeted cytochrome P450 2E1 (P450 MT5) contains an intact N terminus and requires mitochondrial specific electron transfer proteins for activity. J Biol Chem 2001; 276:24680- 24689. DOI: 10.1074/jbc.M100363200

Sangar MC, Bansal S, Avadhani NG. Bimodal targeting of microsomal cytochrome P450s to mitochondria: implications in drug metabolism and toxicity. Expert Opin Drug Metab Toxicol 2010;6(10):1231-1251. DOI: 10.1517/17425255.2010.503955

Mitchell SC. Xenobiotic conjugation with phosphate - a metabolic rarity. Xenobiotica 2016;46:743-756. DOI: 10.3109/00498254.2015.1109161

Semak I, Korik E, Antonova M, Wortsman J, Slominski A. Metabolism of melatonin by cytochrome P450s in rat liver mitochondria and microsomes. J Pineal Res 2008;45:515-

DOI: 10.1111/j.1600-079X.2008.00630.x

Manoj KM. Mitochondrial oxidative phosphorylation: Debunking the concepts of electron transport chain, proton pumps, chemiosmosis and rotary ATP synthesis. arXiv preprint 2017; arxXiv:1703.05826.

Manoj KM. Murburn concept: A facile explanation for oxygen-centered cellular respiration. arXiv preprint 2017; arXiv:1703.05827.



Article Tools
Email this article (Login required)
About The Author

Kelath Murali Manoj
Satyamjayatu: The Science and Ethics Foundation, Kulappully, Shoranur-2 (PO), Palakkad District, Kerala

Font Size