Scientific Online Resource System

Biomedical Reviews

Murburn scheme for mitochondrial thermogenesis

Kelath Murali Manoj, Daniel Andrew Gideon, Vivian David Jacob


The physiology of thermogenesis in mitochondria (mediated by uncoupling protein, UCP) has traditionally been explained as the dissipation of proton gradient across the inner mitochondrial membrane into heat. However, there are differences of opinion on how thermogenesis is achieved by UCPs and the mechanistic theories have not been correlated sufficiently with UCP`s structure. Recent experimental evidence suggests strong correlation of diffusible reactive oxygen species (DROS) with UCP-induced thermogenesis. Further, the mechanistic explanations of mitochondrial oxidative phosphorylation (mOxPhos) were recently revamped with murburn concept, which considers DROS as an obligatory catalytic agent in mOxPhos. Herein, we propose that UCPs (aided by the large pore and positively charged amino acids of aqueous-phase loops) enable protonation and transport of DROS. Thus, UCP facilitates DROS-reactions amongst themselves, forming water and liberating heat around the inner mitochondrial membrane. Thereby, the simple murburn scheme for biothermogenesis integrates structural information of UCP with its attributed physiological function.


structure-function correlation; membrane/respiratory proteins; uncoupling protein; thermogenesis; murburn concept/scheme

Full Text


Nicholls DG, Rial E. A history of the first uncoupling protein, UCP1. J. Bioenerg Biomembr 1999; 31: 399-406. doi:10.1023/A:1005436121005.

Chechi K, Nedergaard J, Richard D. Brown adipose tissue as an anti-obesity tissue in humans. Obes Rev 2014; 15: 92-106. doi:10.1111/obr.12116.

Rousset S, Alves-Guerra M-C, Mozo J, et al. The biology of mitochondrial uncoupling proteins. Diabetes 2004; 53 (Suppl 1): S130-135. doi:10.2337/diabetes.53.2007.S130

Berg JM, Tymoczko JL, Stryer L. Biochemistry. WH Freeman, 2002.

Lehninger A L, Nelson DL, Cox M. Principles of Biochemistry. Palgrave Macmillan Limited, 2004.

Voet D, Voet JG. Biochemistry. Wiley, 2011.

Klingenberg M, Echtay KS, Bienengraeber M, Winkler E, Huang SG. Structure-Function Relationship in UCP1. Int J Obes 1999; 23: S24-S29. doi:10.1038/sj.ijo.0800939.

Kadenbach B. Intrinsic and extrinsic uncoupling of oxidative phosphorylation. Biochim Biophys Acta - Bioenerg 2003; 1604: 77-94. doi:10.1016/S0005-2728(03)00027-6.

Bouillaud F, Alves-Guerra MC, Ricquier D. UCPs, at the interface between bioenergetics and metabolism. Biochim Biophys Acta - Mol Cell Res 2016; 1863: 2443-2464. doi: 10.1016/j.bbamcr.2016.04.013.

Shin H, Ma Y, Chanturiya T, et al. Lipolysis in brown adipocytes us not rssential for cold-induced thermogenesis in mice. Cell Metab. 2017; 26: 764-777.e5. doi:10.1016/j. cmet.2017.09.002.

Schreiber R, Diwoky C, Schoiswohl G, et al. Cold-induced thermogenesis depends on ATGL-mediated lipolysis in cardiac muscle, but not brown adipose tissue. Cell Metab. 2017; 26: 753-763.e7. doi:10.1016/j.cmet.2017.09.004.

Chouchani, E. T. et al. Mitochondrial ROS regulate thermogenic energy expenditure and sulfenylation of UCP1. Nature 2016; 532: 112-116. doi: 10.1038/nature17399.

Kazak L, Chouchani ET, Stavrovskaya IG, et al. UCP1 deficiency causes brown fat respiratory chain depletion and sensitizes mitochondria to calcium overload-induced dysfunction. Proc Natl Acad Sci USA. 2017; 114: 7981- 7986. doi:10.1073/pnas.1705406114.

Jastroch M. Uncoupling protein 1 controls reactive oxygen species in brown adipose tissue. Proc Natl Acad Sci 2017; 114: 201709064. doi: 10.1073/pnas.1709064114.

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.

Manoj KM. Debunking chemiosmosis and proposing murburn concept as the explanation for cellular respiration. Biomed Rev 2017; 28: 35-52. doi:10.14748/bmr.v28.4450.

Manoj KM. Aerobic respiration: Criticism of the proton-centric explanation involving rotary ATP synthesis, chemiosmosis principle, proton pumps and electron transport chain. 2018; 11:1-24. doi: 10.1177/1178626418818442.

Manoj KM, Parashar A, Jacob VD, Ramasamy S. Aerobic Respiration: Proof of concept for the murburn perspective. 2018. doi: 10.1080/07391102.2018.1552896.

Berardi MJ, Shih WM, Harrison SC, Chou JJ. Mitochondrial uncoupling protein 2 structure determined by NMR molecular fragment searching. Nature 2011; 476: 109. doi: 10.1038/nature10257.

Bienert S, Waterhouse A, Beer TAP De, et al. The SWISS-MODEL Repository -- new features and functionality. 2017; 45: 313-319. doi:10.1093/nar/gkw1132.

Kelley LA, Mezulis S, Yates CM, Wass MN, Sternberg MJE. The Phyre2 web portal for protein modeling, prediction and analysis. Nat Protoc 2015; 10: 845-858. doi: 10.1038/nprot.2015.053.

Yang J, Yan R, Roy A, Xu D, Poisson J, Zhang Y. The I-TASSER Suite: protein structure and function prediction. Nat Methods 2015; 12: 7-8. doi:10.1038/nmeth.3213.

Zhao L, Wang S, Zhu Q, Wu B, Liu Z, Yang BO, Chou JJ. Specific interaction of the human mitochondrial uncoupling protein 1 with free long-chain fatty acid.` Structure 2017; 25: 1371-1379. doi: 10.1016/j.str.2017.07.005.

Delano WL. The PyMOL Molecular Graphics System. DeLano Scientific, Palo Alto, CA, USA. 2002. http:// 2002.

Pettersen EF, Goddard TD, Huang CC, et al. UCSF Chimera--a visualization system for exploratory research and analysis. J Comput Chem 2004; 25: 1605-1612. doi:10.1002/jcc.20084.

Chovancova, E. et al. CAVER 3.0: a tool for the analysis of transport pathways in dynamic protein structures. PLoS Comput Biol 2012; 8: e1002708. doi:10.1371/journal. pcbi.1002708.

Yu J, Zhou Y, Tanaka I, Yao M. Roll: a new algorithm for the detection of protein pockets and cavities with a rolling probe sphere. Bioinformatics 2012; 26: 46-52. doi: 10.1093/bioinformatics/btp599.

Skulachev VP. Fatty acid circuit as a physiological mechanism of uncoupling of oxidative phosphorylation. FEBS Lett 1991; 294: 158-162. doi:10.1016/0014- 5793(91)80658-P.

Garlid KD, Orosz DE, Modriansky M, Vassanelli S, Jezek P. On the mechanism of fatty acid-induced proton transport by mitochondrial uncoupling protein. J Biol Chem 1996; 271: 2615-2620. doi:10.1074/jbc.271.5.2615.

Winkler E, Klingenberg M. Effect of fatty acids on H+ transport activity of the reconstituted uncoupling protein. J Biol Chem 1994; 269: 2508-2515.

Rial E, Aguirregoitia E, Jimenez-Jimenez J, Ledesma A. Alkylsulfonates activate the uncoupling protein UCP1: implications for the transport mechanism. Biochim Biophys Acta 2004; 1608: 122-130. doi: 10.1016/j.bbabio.2003.11.001.

Fedorenko A, Lishko PV, Kirichok Y. Mechanism of fatty-acid-dependent UCP1 uncoupling in brown fat mitochondria. Cell 2012; 151: 400-413. doi: 10.1016/j. cell.2012.09.010.

Sanchez-Alavez M, Conti B, Wood MR, et al. ROS and sympathetically mediated mitochondria activation in brown adipose tissue contribute to methamphetamine-induced hyperthermia. Front Endocrinol (Lausanne). 2013; 4: 1-13. doi:10.3389/fendo.2013.00044.

Stier A, Bize P, Habold C, Bouillaud F, Massemin S, Criscuolo F. Mitochondrial uncoupling prevents cold-induced oxidative stress: a case study using UCP1 knockout mice. J Exp Biol 2014; 217: 624-630. doi:10.1242/ jeb.092700.

Echtay KS, Roussel D, St-Pierre J, et al. Superoxide activates mitochondrial uncoupling proteins. Nature 2002; 415: 96-99. doi:10.1038/415096a.

Criscuolo F, Mozo J, Hurtaud C, Nübel T, Bouillaud F. UCP2, UCP3, avUCP, what do they do when proton transport is not stimulated? Possible relevance to pyruvate and glutamine metabolism. Biochim Biophys Acta - Bioenerg 2006; 1757: 1284-1291. doi: 10.1016/j. bbabio.2006.06.002.

Talbot DA, Lambert AJ, Brand MD. Production of endogenous matrix superoxide from mitochondrial complex I leads to activation of uncoupling protein 3. FEBS Lett 2003; 556: 111-115. doi:10.1016/S0014-5793(03)01386- 3.

El-Benna J, Dang PM-C, Perianin A. Peptide-based inhibitors of the phagocyte NADPH oxidase. Biochem Pharmacol 2010; 80: 778-785. doi: 10.1016/j.bcp.2010.05.020.

Joseph G, Gorzalczany Y, Koshkin V, Pick E. Inhibition of NADPH oxidase activation by synthetic peptides mapping within the carboxyl-terminal domain of small GTP-binding proteins. Lack of amino acid sequence specificity and importance of polybasic motif. J Biol Chem 1994; 269: 29024-29031.

Takac I, Schroder K, Zhang L, et al. The E-loop is involved in hydrogen peroxide formation by the NADPH oxidase Nox4. J Biol Chem 2011; 286: 13304-13313. doi:10.1074/ jbc.M110.192138.

Gideon DA, Kumari R, Lynn AM, Manoj KM. What is the functional role of N-terminal transmembrane helices in the metabolism mediated by liver microsomal cytochrome P450 and its reductase? Cell Biochem Biophys 2012; 63: 35-45. doi: 10.1007/s12013-012-9339-0.

Monne M, Daddabbo L, Gagneul D, Obata T, Hielscher B, Palmieri L, et al. Uncoupling proteins 1 & 2 (UCP1 & UCP2) from Arabidopsis thaliana are mitochondrial transporters of aspartate, glutamate, and dicarboxylates. J Biol Chem 2018; 293: 4213-4227. doi: 10.1074/jbc. RA117.000771.

Manoj KM, Gade SK, Mathew L. Cytochrome P450 reductase: a harbinger of diffusible reduced oxygen species. PLoS One 2010; 5: e13272. doi:10.1371/journal. pone.0013272.

Manoj KM, Gade SK, Venkatachalam A, Gideon DA. Electron transfer amongst flavo- and hemo-proteins: diffusible species effect the relay processes, not protein- protein binding. RSC Adv 2016; 6: 24121-24129. doi: 10.1039/C5RA26122H.

Parashar A, Gade SK, Potnuru M, Madhavan N, Manoj KM. The curious case of benzbromarone: insight into super-inhibition of cytochrome P450. PLoS One 2014; 9: e89967. doi:10.1371/journal.pone.0089967.

Parashar A, Gideon DA, Manoj KM. Murburn Concept: A Molecular explanation for hormetic and idiosyncratic dose responses. Dose Response 2018; 16:1559325818774421. doi:10.1177/1559325818774421.

Sawyer DT, Valentine JS. How super is superoxide? Acc Chem Res 1981; 14: 393-400. doi: 10.1021/ar00072a005.

Kanematsu S, Asada K. Superoxide dismutase. In: Molecular Aspects of Enzyme Catalysis, eds. T Fukui, K Soda. Weinheim: Wiley-VCH Verlag GmbH. 1994; 191-210.

Buxton GV, Greenstock CL, Helman, WP, Ross AB. Critical review of rate constants for reactions of hydrated electrons, hydrogen atoms and hydroxyl radicals (⋅OH/⋅O−) in aqueous solution. J Phys Chem Ref Data 1988; 17(2): 513-886. doi: 10.1063/1.555805.

Gutowski M, and Kowalczyk S. A study of free radical chemistry: their role and pathophysiological significance. Acta Biochim. Pol. 2013; 60(1): 1-16.

Bevan RM, Butler PJ. The effects of temperature on the oxygen consumption, heart rate and deep body temperature during diving in the tufted duck Aythya fuligula. J Exp Biol 1992; 163: 139-151.



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

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

Daniel Andrew Gideon
Satyamjayatu: The Science and Ethics Foundation, Kulappully, Shoranur-2 (PO), Kerala, India

Vivian David Jacob
Satyamjayatu: The Science and Ethics Foundation, Kulappully, Shoranur-2 (PO), Kerala, India

Font Size