What is the Role of Lipid Membrane-embedded Quinones in Mitochondria and Chloroplasts? Chemiosmotic Q-cycle versus Murburn Reaction Perspective
Authors: Kelath Murali Manoj
Abhinav Parashar
Daniel Andrew Gideon
Journal: Cell Biochemistry and Biophysics (2021)
Discipline: BIOLOGY & BIOCHEMISTRY
Keywords: Q-cycle; chemiosmosis; cytochrome b 6 f; murburn concept; plastoquinone
Affiliations: Satyamjayatu: The Science & Ethics Foundation, Kulappully, Shoranur-2 (PO), Palakkad, Kerala, 679122, India. ., Satyamjayatu: The Science & Ethics Foundation, Kulappully, Shoranur-2 (PO), Palakkad, Kerala, 679122, India., Department of Biotechnology, Vignan's Foundation for Science, Technology & Research, Vadlamudi, Guntur, 522213, India. .

Abstract:  Quinones are found in the lipid membranes of prokaryotes like E. coli and cyanobacteria, and are also abundant in eukaryotic mitochondria and chloroplasts. They are intricately involved in the reaction mechanism of redox phosphorylations. In the Mitchellian chemiosmotic school of thought, membrane-lodged quinones are perceived as highly mobile conveyors of two-electron equivalents from the first leg of Electron Transport Chain (ETC) to the 'second pit-stop' of Cytochrome bc1 or b6f complex (CBC), where they undergo a regenerative 'Q-cycle'. In Manoj's murburn mechanism, the membrane-lodged quinones are perceived as relatively slow-moving one- or two- electron donors/acceptors, enabling charge separation and the CBC resets a one-electron paradigm via 'turbo logic'. Herein, we compare various purviews of the two mechanistic schools with respect to: constraints in mobility, protons' availability, binding of quinones with proteins, structural features of the protein complexes, energetics of reaction, overall reaction logic, etc. From various perspectives, the murburn mechanism appeals as a viable alternative explanation well-rooted in thermodynamics/kinetics and one which lends adequate structure-function correlations for the roles of quinones, lipid membrane and associated proteins. 

Retracted: No

PubPeer comments:
 This recently published paper claims to show inconsistencies and insurmountable problems in the traditional description of the Q-cycle. In spite of its ambitious goals, this paper fails to properly engage with the extant literature and is, mostly, a series of strawmen arguments based on lack of structural knowledge, basic misunderstandings, mis-quoting of the literature they cite as u201csupportu201d and thermodynamic errors. A proper dissection of all of those flaws could easily become as lengthy as the original paper, but I will try to be brief and will only mention the most salient errors. In the rest of this report, direct quotations of the paper will be made **in bold**, and sequentially addressed. Many other errors are present in this manuscript, but these will be enough to show its fundamentally flawed nature. In the second paragraph, authors state as one of their motivations: u201c**In the light of the simple fact that the vast majority of life forms evolved around oxygen, Manoj deduced that oxygen must have a greater physiological role than what is attributed to it by the ETC-CRAS hypothesis**u201d This simple sentence is wrong in many levels: A) it is well-known that metabolic diversity among anaerobes is extremely high and that when photosynthesis began to release large amounts of oxygen into the atmosphere, most of the then-extant (necessarily anaerobic) lifeforms became extinct (Hodgskiss et al., 2019)u2060u2060:current perceptions of u201caerobic supremacyu201d are at least in part a consequence of the fact that the organisms who could not cope with oxygen died out or were relegated to oxygen-poor ecological niches and were therefore prevented from evolving into the degrees of complexity we find in some branches of the Eukaryota. B) contrary to Manoju2019s perception, the role attributed to oxygen in the standard textbook description of Bioenergetics is massive, and it easily overwhelms the role of any other terminal electron-acceptor due to its high redox potential. C) the whole sentence is a non-sequitur because the second part of the sentence does not depend on the first: one could equally argue, using the u201clogicu201d of the quoted sentence that u201cIn the light of the simple fact that the vast majority of life forms evolved around DINITROGEN, this gas must have a greater physiological role in all cells than admitted by its description as a u201cvery unreactive gasu201d u201d or u201cIn the light of the simple fact that the vast majority of life forms evolved around WATER, this molecule must have a greater physiological role in all cells than admitted by its description as u201csolventu201d u201d . Authors then note that u201c**acclaimed textbooks and or reviews portray quite distinct mechanisms stoichiometries for QCBC. For example: (i) While Voet portrays that CoQ translocates protons into intermembrane space (IMS) ([20]), Lehninger depicts Cyt. bc1 as the protein, which performs this function in mitochondria [21]. (ii) A similar picture is noted for the chloroplast system too wherein Ahern shows PQ relaying protons into thylakoid lumen [22] whereas Lodishu2019s text shows Cyt. b6f discharging this role [23].**u201d There is no contradiction between the descriptions of the Voet and Lehninger texbooks: contrary to the authoru2019s claims, pages 847-850 of Voet, 4th edition, clearly explain the whole Q-cycle and how each of the ubiquinone molecules interacts with cytochrome bc1. Ahernu2019s u201cBiochemistry Free Easyu201d is an introductory text without excessive detail (for example, it does not depict how the Q-Cycle operates), but it does state that plastoquinone transfers electrons to b6f. Offering these citations as support to any kind of controversy regarding the Q-cycle is completely unjustified. It is a basic tenet of proper scholarly methodology that references to supporting materials should be relevant and exact. Some nuance will frequently be lost in the paraphrase for a long text into a short summary, and that is completely acceptable. Offering as support a citation which contradicts the point that the authors want it to support is not acceptable. There is also no controversy regarding the number of protons released in the Q-cycle: all workers agree that two protons are taken up by Q at the matrix-facing Qi site and 4 protons are expelled from two QH2 to the inter-membrane space at the Qo site. Early investigations got conflicting results because some of them were computing protons taken up from the matrix whereas others were instead measuring the number of protons released to the inter-membrane space . u201c**The three examples above need to be placed in the context that yet another reputed researcher with long-standing expertise on Complex III had specifically pointed out (with both monomers and dimers) that there is no explicit evidence that it functions as a proton pump [30].** u201d The 34 year-old reference used as support is missing the wealth of structural evidence gathered since. By relying on it and disregarding that evidence, authors are simply confusing two different mechanisms for proton translocation across the membrane: u201ctraditionalu201d proton pumps (which could still be regarded as a possibility in 1986) and redox loops (conclusively confirmed since(Crofts et al., 2006)u2060). The Q-cycle is a redox loop, and therefore there is no inconsistency in stating that proton translocation occurs in complex III even if this complex is not a u201ctraditionalu201d proton pump (like complex I). u201c**Similarly, there seems to be difference of opinion whether Complex I is a sodium pump or proton pump or both**u201d Authors here present the observation of a sodium-pumping complex I in K. pneumoniae as a general observation regarding all instances of complex I. This is not exact. Regarding the diffusion of quinones in the lipid membrane, authors state u201c**Therefore, the bulky hydrophobic substituent group (which also has several methyl substitutions at the sp2 carbon of each isoprenoid unit) of the quinones would make its translational diffusion through the viscous hydrophobic region difficult, when compared to the relatively facile motility of the unsubstituted shorter fatty acyl chains. [..] While the relatively hydrophobic quinone could be solubilized within the lipid phase for diffusion, the products (ubisemiquinone and ubiquinol) would be positioned with their polar head- groups outside the lipid phase (Fig. 1). Therefore, the products (the actual mobile electron carriers of the ETC- CRAS proposal) must translate along the lipid plane by colliding sliding along with the polar headgroups of the membrane phase, and dragging their bulky tail.** u201d As usual in their oeuvre, authors present their speculations and intuitions without checking the literature to see if those issues have been addressed previously. Experimental measurements have shown that short tailed CoQ diffuse only slightly faster than ubiquinones with a long tail (Di Bernardo et al., 1998; Marchal et al., 1998)u2060u2060 and that the quinol and quinone forms have identical diffusion coefficients(Marchal et al., 1998)u2060. Molecular dynamics simulations (Kaurola et al., 2016) have shown that the quinol form of very short-tailed CoQ cross the center of the membrane less easily than those of CoQ10, that the lateral diffusion of the quinone forms is mostly independent of tail size(Galassi Arantes, 2015) and that lateral diffusion of the quinol forms is, at most, faster, than that of the quinone form (although that special test was only performed with the shorter-chain uniquinone). The computational data show that the magnitude of the diffusion coefficients of CoQ in the bilayer is basically identical to that the other membrane lipids (Galassi Arantes, 2015; Su00f6derhu00e4ll Laaksonen, 2001)u2060u2060 u201c**Such a deterministic journey of quinols from the first pit stop of ETC (Complexes 1 II or Photosystem II) to the next pit stop of CBC would have little thermodynamic drive, other than upholding the mandate of ETC-CRAS scheme. Further, the translation would also be kinetically disadvantaged, with respect to the millisecond scale kinetics of NADH oxidation (oxygen consumption in mitochondria) or NADPH production (oxygen evolution in chloroplasts) **u201d The movement of lipids (such as ubiquinone ubiquinol in the membrane is not deterministic, but a random walk Brownian motion like any other diffusion process. There is no reason to expect (or require) any kind of u201cthermodynamic driveu201d. Authors are also well aware (as any reader can see from their publication in J. Biomol. Struct. Dynamics (Manoj, 2020) u2060 of the existence of supra-molecular complexes of complex I complex III complex IV called respirasomes which, by placing complex I in strong proximity to complex III, are expected to greatly increase the rate of ubiquinone diffusion from complex I to complex III. It is therefore baffling to find them arguing otherwise. u201c**For example: the experimentally calculated PQu2019s diffusion coefficient of 0.01u20130.3 u03bcm2 s within thylakoid membranes [38, 39] gives us a linear displacement of only ~0.1u20135 u00c5 ms . This implies that the bulky quinone is practically u2018immobileu2019 with respect to the distance separating the protein complexes within the reaction timescales.**u201d The mean-squared displacement in a 2D-Browninan motion is 4 * Diffusion coefficient * t. The mean-squared displacement upon a 1 millisecond motion of a molecule with coefficient of 0.01-0.3 u03bcm2 s is therefore between 4*10^-5 u03bcm2 and 1.2*10^-3 u03bcm2, which translates (upon taking the square root), to between 63 and 346 u00c5, in marked contrast to the 0.1-5 u00c5 claimed by the authors. Their conclusions of quinone immobility (and therefore the justification for their perceived need of a different mechanism) are therefore based in a completely erroneous basis. u201c**Similar studies with CoQ had shown that diffusion rate of these molecules within the mitochondrial membrane was low and would be rate limiting for the ETC-CRAS proposal [40, 41]. These qualitative considerations and quantitative limitations question the physiological relevance the ETC-CRAS hypothesis.**u201d This reasoning is quite unclear: after all, any process composed of multiple steps must necessarily have one step that is slower than the others (i.e. a rate-limiting step). Authors seem to imply that finding a rate-limiting step throws into question the whole mechanism, but that is not a correct inference. Regardless, authors do not show any data to support their claim that the diffusion rate of CoQ would be inconsistent with the physiological oxidative phosphorylation rates. Moreover, the references the authors cite do not fully support their claims: ref. 40 states the exact opposite (u201c*The diffusion coefficients established in this study reveal that the theoretical diffusion-controlled collision frequencies of all redox components ARE GREATER [emphasis mine] than their experimental maximum (uncoupled) turnover numbers.*u201d ) while ref. 41 , which focuses on succinate-linked electron transport, found that u201c*the rates of diffusion and appropriate concentrations of redox components limit the maximum rates of electron transport in the inner membrane*u201d and detected no incompatibility between the rate of ubiquinone diffusion ad the electron-transfer rates. u201c**In all these proteins, the precise modalities of interactions are still not clear. For exampleu2014(i) The bulkier isoprenoid substituted quinones showed poor docking energies and conformations with Complexes I through III [8]. (ii) Complex Iu2019s purported quinone binding site is located several Angstroms into the matrix-ward arm [33]. . It would be physiologically improbable to expect the quinone head group to make its way into the protein body and dock at this site, and detach after the formation of quinol, enabling yet another fresh quinone molecule to dock in lieu **u201d It is surprising that authors completely fail to mention the abundant structural, kinetic and computational information regarding the quinone binding site (e.g. (Warnau et al., 2018 and references therein)u2060, which include detailed simulations of quinone movement through the tunnel and precise determinations of the relevant potential-of-mean-force, and instead decide to rely on molecular docking. Molecular docking is indeed a powerful technique, which is hampered by the high imperfection of the pose scoring functions and by the need to use very high quality structures where enough structural flexibility has been introduced. Whereas sidechain flexibility in the putative docking site (which massively increases computational cost) is often not needed when docking small ligands, attempting to dock large ligands (like ubiquinone) in a rigid site will not meet any success due to the overwhelming probability that, when the site is empty, thermal fluctuations of the sidechains will place at least a few of them in conformations where they partially block some critical portion of the volume. Authorsu2019 lack of success when docking ubiquinone is therefore due to the limitation of the docking method used, rather than to any feature of the active site. u201c**Also, one wonders how and where from the CoQ molecules find two protons for making the quinols, deep within the hydrophobic domain of the proteinu2019s transmembrane domain**.u201d Again, authors show their unfamiliarity with the literature and with the protein structures, since His-38(Nqo4) and Tyr-87(Nqo4) have been proposed to act as the proton donors. Authors repeat that claim u201c**(ii) Some reviews in the past have vouched that mitochondrial Complex II has two CoQ-binding sites, and therefore, this complex may also be involved in Q-cycle [42]. Even in this protein, it is not known how CoQ could avail protons for forming the quinol, post reduction.**u201d in reference to complex II, where an examination of the PDB:1ZOY crystal structure shows that Tyr91 and Ser42 are positioned in H-donating distance relative to the quinone oxygens. u201c**Further, the electron receiver of heme bL is quite far from the CoQH2 site and it is inconceivable how the reverse circuitry (electrons flowing from CoQH2 back to CoQ) can be achieved, as it would be u2018uphillu2019 in a real u2018ETC circuitu2019**.u201d Tuning of CoQ redox potential by the protein environment has been extensively studied (e.g. (Crofts et al., 2006)u2060 ). Like in flavins, the potential can be selectively tuned by active sites which preferentially stabilize one form or the other. u201c**ETC-CRAS becomes even more unconvincing with respect to the newly unraveled structures of supramolecular complexes such as respirasomes [8], as the CoQ CoQH2 would have to navigate through protein frameworks to reach its purported targets binding sites.**u201d Analysis of the respirasome structure, in contrast to the authorsu2019claims, shows that there is a large enough portion of membrane between the complex I CoQ binding site and the CoQ2 binding site in complex III. Ubiquinol does not have to u201cnavigateu201d any specially intricate framework in the respirasome compared to the u201cfree complexu201d situation. ![file] ![file] u201c**Prima facie, we pointed out multiple times that there are very little free protons present in the microdimensioned organelles to serve the purported proton pumps [4, 5, 8, 9]. Therefore, the Mitchellian u2018proton pumpsu2019 cannot start from the initial state**u201d As many protons as needed can always be provided by water dissociation into H+ and HO-. This is a fundamental consequence of chemical equilibria which the authors continually neglect. u201c**Next, it defies electrochemical or thermodynamic logic that the phase maintained at a positive potential also gets the protons and electrons continuously**u201d No logic-defying steps occur in the standard explanation of bioenergetics. Protons are ejected to the u201cpositive potential phaseu201d through the expenditure of free energy released by electron-transfer in the proton-translocating complexes. This is explained in any introductory Biochemistry textbook. References: Crofts, A. R., Lhee, S., Crofts, S. B., Cheng, J., Rose, S. (2006). Proton pumping in the bc1 complex: A new gating mechanism that prevents short circuits. Biochimica et Biophysica Acta (BBA) - Bioenergetics, 1757(8), 1019u20131034. https: doi.org 10.1016 j.bbabio.2006.02.009 Di Bernardo, S., Fato, R., Casadio, R., Fariselli, P., Lenaz, G. (1998). A high diffusion coefficient for coenzyme Q 10 might be related to a folded structure. FEBS Letters, 426(1), 77u201380. https: doi.org 10.1016 S0014-5793(98)00313-5 Galassi, V. V., Arantes, G. M. (2015). Partition, orientation and mobility of ubiquinones in a lipid bilayer. In Biochimica et Biophysica Acta - Bioenergetics (Vol. 1847, Issue 12, pp. 1560u20131573). https: doi.org 10.1016 j.bbabio.2015.08.001 Hodgskiss, M. S. W., Crockford, P. W., Peng, Y., Wing, B. A., Horner, T. J. (2019). A productivity collapse to end Earthu2019s Great Oxidation. Proceedings of the National Academy of Sciences, 116(35), 17207u201317212. https: doi.org 10.1073 pnas.1900325116 Kaurola, P., Sharma, V., Vonk, A., Vattulainen, I., Ru00f3g, T. (2016). Distribution and dynamics of quinones in the lipid bilayer mimicking the inner membrane of mitochondria. Biochimica et Biophysica Acta (BBA) - Biomembranes, 1858(9), 2116u20132122. https: doi.org 10.1016 j.bbamem.2016.06.016 Manoj, K. M. (2020). Refutation of the cation-centric torsional ATP synthesis model and advocating murburn scheme for mitochondrial oxidative phosphorylation. Biophysical Chemistry, 257, 106278. https: doi.org 10.1016 j.bpc.2019.106278 Manoj, K. M., Parashar, A., David Jacob, V., Ramasamy, S. (2019). Aerobic respiration: proof of concept for the oxygen-centric murburn perspective. Journal of Biomolecular Structure and Dynamics, 37(17), 4542u20134556. https: doi.org 10.1080 07391102.2018.1552896 Manoj, K. M., Ramasamy, S., Parashar, A., Gideon, D. A., Soman, V., Jacob, V. D., Pakshirajan, K. (2020). Acute toxicity of cyanide in aerobic respiration: Theoretical and experimental support for murburn explanation. Biomolecular Concepts, 11(1), 32u201356. https: doi.org 10.1515 bmc-2020-0004 Marchal, D., Boireau, W., Laval, J. M., Moiroux, J., Bourdillon, C. (1998). Electrochemical measurement of lateral diffusion coefficients of ubiquinones and plastoquinones of various isoprenoid chain lengths incorporated in model bilayers. Biophysical Journal, 74(4), 1937u20131948. https: doi.org 10.1016 S0006-3495(98)77902-0 Su00f6derhu00e4ll, J. A., Laaksonen, A. (2001). Molecular dynamics simulations of ubiquinone inside a lipid bilayer. Journal of Physical Chemistry B, 105(38), 9308u20139315. https: doi.org 10.1021 jp011001w Warnau, J., Sharma, V., Gamiz-Hernandez, A. P., Di Luca, A., Haapanen, O., Vattulainen, I., Wikstru00f6m, M., Hummer, G., Kaila, V. R. I. (2018). Redox-coupled quinone dynamics in the respiratory complex I. Proceedings of the National Academy of Sciences, 115(36), E8413u2013E8420. https: doi.org 10.1073 pnas.1805468115 , 
 I cannot respond to pseudo anonymous persons. The post is malicious!! , 
 It is a good idea for the advancement of science to have credible debates wherein the identity of the debaters are established and others readers can attribute a falsifiable opinion to a person. When this is not the premise, anybody takes a potshot at anything credible. For example- when someone says protons can be furnished by water owing to Le-Chatelier s principle, it is a nonsense that anyone with basic foundations in theory and experiment can call out. If water can give protons as much as needed, then addition of alkali should keep pH constant! If someone really cares for this subject, they may read my update in the field at the following publications: Manoj KM* Bazhin NM (2021) Progress in Biophysics and Molecular Biology. The murburn precepts of aerobic respiration and redox homeostasis. doi: 10.1016 j.pbiomolbio.2021.05.010 Gideon DA, et al. Manoj KM* (2021) Journal of Biomolecular Structure and Dynamics. Mechanism of electron transfers mediated by cytochromes c and b5 in mitochondria and endoplasmic reticulum: Classical and murburn perspectives. doi: 10.1080 07391102.2021.1925154 Manoj KM* (2020) Biomedical Reviews 31, 135. In defense of the murburn explanation for aerobic respiration. (Includes a Supplementary Information file that points out the lack of consensus in the field.) , 
 I forgot something: My critiques don t seem to address the conclusive arguments for murburn and against the classical explanations I presented in : Manoj KM, Ramasamy S, Parashar A, Gideon DA, Soman V, Jacob VD, and Pakshirajan K. (2020a). Acute toxicity of cyanide in aerobic respiration: Theoretical and experimental support for murburn explanation. Biomolecular Concepts (De Gruyter) 11, 32-56. doi: 10.1515 bmc-2020-0004 (Published on 17th March, 2020) , 
 Also, the following unpublished arguments leave little for the classical coterie to hold on.... Manoj, K. M., Gideon, D. A., Parashar, A. (2020). Refuting the ideas advocated by Yuly et al. (PNAS, Sep. 2020): u2018Universal free energy landscapesu2019 and u2018deterministic electron-relay circuitryu2019 are unsustainable within membrane-embedded cytochrome b protein complexes involved in bioenergetic routines. OSF Preprints. https: doi.org 10.31219 osf.io 4vmct , 
 Last time I tried to post a comment after logging in as the author, it asked me to verify my identity repeatedly and did not send the verification email either to my account. I guess this website is just a tool of some powerful people in the establishment. All that these detracting peers have to do to bring my group s work down legitimately is write to the journal office where the papers were published and offer the editor their rebuttals to what we have found and advocated. Since our pursuits are anti-establishment, they can easily get their works published. But then, with that exercise, they will have to reveal their identity. That will not allow them to make a volte face when our theory prevails. Yet, I respect Pedro Silva s approach for coming out in the open to defend chemiosmosis, but he has not done any justice to the volume of arguments evidence we presented against the classical bioenergetics paradigm. Further, he has not addressed the volume of works that supports the murburn theory either. And he shall go down in history as a vain martyr, sacrificed by the puppeteers that seem to shepherd goad such pursuits. Pubpeer can go ahead and allow anonymous people to malign my works. But your progeny will study and benefit out of the critical insights my group s works have offered. This is sad! There is no accountability or transparency in your system. People write comments like they understand the work and pose to be experts, all the while ovelooking and slanting meticulous works and systematically waylaying somebody s legitimate progression. One goes through dozens of journals to have a counter-current paper published. Then there is this platform where every Tom, Dick and Harry get to pull down such works..... I shall not defend my works anymore on this portal, as this is a vain exercise that just wastes my time and unnecessarily gives the vanities here some credibility. , 
 I see that my comments were allowed to be posted now (at least for this paper), after I protested with the portal. (The other papers, the more crucial ones on chemiosmosis, which point out the redundancy disclaimed writings of Silva, remain filtered screened by moderators.) In this case, regarding the role of quinones, one can just see the bottom figure that the peer has presented (side view). Biologists may not understand the physico-chemical evidence and arguments we have presented. But surely, seeing is believing. Quinones and quinols are molecules present in lipid phase. See the location of the quinone heads, as per the classical view. It is about 2 nm into the protein s matrix subtending arm that contains the FeS centers. How is a quinone going to dock there, get reduced as quinol, move out and migrate to the quinol docking site of Complex III? How is the quinone going to be differentiated from the quinol? Is a quinone quinol a snake, that will deterministically leave lipid membrane to burrow through protein infrastructures to reach the purported binding loci? How can the electron transfers in the matrix arm be connected to the purported proton pumping activity in the foot? My proposals are fairly simple, in this regard. There is no need for quinones and quinols to be deterministically bound at specific loci on the membrane complexes. If mobility was a deterministic criteria, CoQ10 would not be the predominant quinone in the membrane, the smaller quinones could have served this purpose better! Chemiosmosis is just a mirage, and the quinone cycle is a mirage created to sustain the mirage. If seeing is believing, the purported binding sites locations within the complexes, as shown by my misplaced peers should ring alarm bells to any discerning reader. People, you must read my works, which are available at https: scholar.google.co.in citations?hl=en user=gvBtBHYAAAAJ view_op=list_works sortby=pubdate , 
  Acknowledgements The work was powered by Satyamjayatu: The Science Ethics Foundation. What does  powered mean? Is this the equivalent of funding? , 
 Please try to focus on the real aspects of the work, if you can! Here is the article s attributes: ![file] I am not going to indulge you folks at this portal any more................. This is too much!! I don t accept your policing. If you want to use the insights I give you, use it and reorient yourselves, and stop yourselves from wasting taxpayers hard-earned money. , 
 #8 This u201corganizationu201d appears to have a rudimentary website: https: www.satyamjayatu.com Material there suggests that Dr. Manoj may be the founder and sole member of this business which seems to offer tutoring or teaching services; the site includes what may be a list of former students. Much about this is unclear, but it is clear that Dr. Manoj is intent on challenging the scientific consensus in this field. ![file] , 
 It is factually inaccurate to state that  It is clear that Dr. Manoj is intent on challenging the scientific consensus in this field. Correct- Dr. Manoj is challenging the confusion and false perceptions prevailing in the field and bringing in clarity! Manoj, K. M. (2020). In defense of the murburn explanation for aerobic respiration. Biomedical Reviews, 31, 135u2013160. https: doi.org 10.14748 bmr.v31.7713 Manoj, K. M. (2020). Supplementary information in defense of murburn explanation for aerobic respiration. Biomedical Reviews, 31, 135u2013160. http: dx.doi.org 10.14748 bmr.v31.7714 Manoj, K. M. (2020). Murburn concept: A paradigm shift in cellular metabolism and physiology. Biomolecular Concepts, 11(1), 7u201322. https: doi.org 10.1515 bmc-2020-0002 There is no consensus in field. And Science is a pursuit of reason, not consensus.... That idea is called democracy. When you folks cannot deal with the simple  seeing is believing kind of arguments I pointed out using your own material (refer post #7), you go for my credibility! Also, you may feel free to defame my collaborators who are Professors in reputed institutions of India, Russia, China and Japan. I choose not to indulge in such vanities anymore. You folks are vain and I repeat- you are not worth my time! ,